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He Y, Yang Z, Guo D, Luo C, Liu Q, Xian L, Yang F, Huang C, Wei Q. The multifaceted nature of SUMOylation in heart disease and its therapeutic potential. Mol Cell Biochem 2025:10.1007/s11010-025-05286-z. [PMID: 40287894 DOI: 10.1007/s11010-025-05286-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 04/06/2025] [Indexed: 04/29/2025]
Abstract
SUMOylation (SUMO), a crucial post-translational modification, is implicated in the regulation of diverse biological processes and plays a pivotal role in both the maintenance of cardiac function and progression and treatment of heart disease. Here, we reviewed the mechanisms by which SUMO-related various aspects of cardiac function and disease, including cardiac hypertrophy, heart failure, ischemia-reperfusion injury, and myocardial infarction. Furthermore, we highlight its potential as a therapeutic target.
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Affiliation(s)
- Ying He
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhijie Yang
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Dan Guo
- Medical College, Guangxi University, Nanning, Guangxi, China
| | - Cheng Luo
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Qiaoqiao Liu
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Lei Xian
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Fan Yang
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China.
- Liuzhou Key Laboratory of Primary Cardiomyopathy in Prevention and Treatment, Liuzhou, Guangxi, China.
| | - Chusheng Huang
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Qingjun Wei
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
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Matthees ESF, Kletzin LE, Löbbert A, Hoffmann JS, Große C, Gossert AD, Hoffmann C. Isoprenaline shows unique kinase dependencies in stimulating β 1AR-β-arrestin2 interaction compared to endogenous catecholamines. Mol Pharmacol 2025; 107:100041. [PMID: 40354729 DOI: 10.1016/j.molpha.2025.100041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/21/2025] [Accepted: 04/12/2025] [Indexed: 05/14/2025] Open
Abstract
The β1-adrenergic receptor (β1AR) is an essential G protein-coupled receptor in the heart. Its dysregulation represents a hallmark of cardiac diseases. Studies have identified a unique mode of β-arrestin interaction, where β1AR briefly engages with β-arrestins before catalytically accumulating them at the plasma membrane (PM) independently of the receptor. Although receptor phosphorylation crucially impacts β-arrestins, the contributions of specific kinases vital in β1AR regulation remain unclear. Here, we employed G protein-coupled receptor kinase (GRK) GRK2/3/5/6 knockout cells and the protein kinase A inhibitor H89 in bioluminescence resonance energy transfer-based assays to systematically assess GRKs and protein kinase A in direct β-arrestin2 recruitment to β1AR and β-arrestin2 translocation to the PM. Furthermore, we compared the effects of the synthetic agonist isoprenaline with the endogenous catecholamines: epinephrine and norepinephrine. We observed pronounced differences in their kinase dependencies to mediate β-arrestin2 translocation to the PM. Upon isoprenaline stimulation, GRKs strongly influenced β-arrestin2 translocation to the PM but had no effect on direct β-arrestin2 recruitment to β1AR. Additionally, in a GRK2-specific context, protein kinase A inhibition primarily reduced the efficacy of isoprenaline for β-arrestin2 translocation, whereas for GRK5, it decreased potency. Strikingly, these kinase-dependent effects were absent for epinephrine and norepinephrine, suggesting distinct underlying molecular mechanisms for β-arrestin2 accumulation at the PM. This observation could be explained by agonist-specific differences in receptor conformational rearrangements, as suggested by distinct changes in the NMR spectra of β1AR. Our findings highlight that synthetic and endogenous ligands induce distinct molecular mechanisms in β1AR regulation, emphasizing the need to consider these differences when translating molecular insights into physiological contexts. SIGNIFICANCE STATEMENT: Our findings reveal mechanistic differences in β1-adrenergic receptor-mediated catalytic activation of β-arrestin2 by synthetic and endogenous agonists, driven by distinct G protein-coupled receptor kinases and protein kinase A dependencies. Although β-arrestin2 translocation to the PM occurred to similar extents with isoprenaline, epinephrine, and norepinephrine, kinase involvement was crucial only upon Iso stimulation of β1-adrenergic receptor. By elucidating these ligand-specific pathways, this study advances our understanding of β1-adrenergic receptor signaling and regulation while additionally highlighting the importance of considering these differences when translating molecular insights into pathophysiological contexts.
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Affiliation(s)
- Edda S F Matthees
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena, Germany.
| | - Luca E Kletzin
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena, Germany
| | - Arnelle Löbbert
- Department of Biology, Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
| | - Jana S Hoffmann
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena, Germany
| | - Carolin Große
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena, Germany
| | - Alvar D Gossert
- Department of Biology, Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
| | - Carsten Hoffmann
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena, Germany.
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Zhao M, Cao N, Gu H, Xu J, Xu W, Zhang D, Wei TYW, Wang K, Guo R, Cui H, Wang X, Guo X, Li Z, He K, Li Z, Zhang Y, Shyy JYJ, Dong E, Xiao H. AMPK Attenuation of β-Adrenergic Receptor-Induced Cardiac Injury via Phosphorylation of β-Arrestin-1-ser330. Circ Res 2024; 135:651-667. [PMID: 39082138 DOI: 10.1161/circresaha.124.324762] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND β-adrenergic receptor (β-AR) overactivation is a major pathological cue associated with cardiac injury and diseases. AMPK (AMP-activated protein kinase), a conserved energy sensor, regulates energy metabolism and is cardioprotective. However, whether AMPK exerts cardioprotective effects via regulating the signaling pathway downstream of β-AR remains unclear. METHODS Using immunoprecipitation, mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we determined whether AMPK phosphorylates β-arrestin-1 at serine (Ser) 330. Wild-type mice and mice with site-specific mutagenesis (S330A knock-in [KI]/S330D KI) were subcutaneously injected with the β-AR agonist isoproterenol (5 mg/kg) to evaluate the causality between β-adrenergic insult and β-arrestin-1 Ser330 phosphorylation. Cardiac transcriptomics was used to identify changes in gene expression from β-arrestin-1-S330A/S330D mutation and β-adrenergic insult. RESULTS Metformin could decrease cAMP/PKA (protein kinase A) signaling induced by isoproterenol. AMPK bound to β-arrestin-1 and phosphorylated Ser330 with the highest phosphorylated mass spectrometry score. AMPK activation promoted β-arrestin-1 Ser330 phosphorylation in vitro and in vivo. Neonatal mouse cardiomyocytes overexpressing β-arrestin-1-S330D (active form) inhibited the β-AR/cAMP/PKA axis by increasing PDE (phosphodiesterase) 4 expression and activity. Cardiac transcriptomics revealed that the differentially expressed genes between isoproterenol-treated S330A KI and S330D KI mice were mainly involved in immune processes and inflammatory response. β-arrestin-1 Ser330 phosphorylation inhibited isoproterenol-induced reactive oxygen species production and NLRP3 (NOD-like receptor protein 3) inflammasome activation in neonatal mouse cardiomyocytes. In S330D KI mice, the β-AR-activated cAMP/PKA pathways were attenuated, leading to repressed inflammasome activation, reduced expression of proinflammatory cytokines, and mitigated macrophage infiltration. Compared with S330A KI mice, S330D KI mice showed diminished cardiac fibrosis and improved cardiac function upon isoproterenol exposure. However, the cardiac protection exerted by AMPK was abolished in S330A KI mice. CONCLUSIONS AMPK phosphorylation of β-arrestin-1 Ser330 potentiated PDE4 expression and activity, thereby inhibiting β-AR/cAMP/PKA activation. Subsequently, β-arrestin-1 Ser330 phosphorylation blocks β-AR-induced cardiac inflammasome activation and remodeling.
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Affiliation(s)
- Mingming Zhao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Ning Cao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital (N.C.), Capital Medical University, Beijing, China
| | - Huijun Gu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Jiachao Xu
- Laboratory for Clinical Medicine (N.C.), Capital Medical University, Beijing, China
| | - Wenli Xu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China (W.X., E.D., H.X.)
| | - Di Zhang
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies (D.Z., Zhiyuan Li), Peking University, Beijing, China
| | - Tong-You Wade Wei
- Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (T.-Y.W.W., J.Y.-J.S.)
| | - Kang Wang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Ruiping Guo
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Hongtu Cui
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Xiaofeng Wang
- Laboratory of Inflammation and Vaccines, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China (X.W.)
| | - Xin Guo
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Zhiyuan Li
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies (D.Z., Zhiyuan Li), Peking University, Beijing, China
| | - Kangmin He
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (J.X., K.H.)
- University of Chinese Academy of Sciences, Beijing, China (K.H.)
| | - Zijian Li
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - Youyi Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
| | - John Y-J Shyy
- Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (T.-Y.W.W., J.Y.-J.S.)
| | - Erdan Dong
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- Institute of Cardiovascular Sciences (E.D.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China (W.X., E.D., H.X.)
| | - Han Xiao
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.), Peking University, Beijing, China
- National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Beijing Key Laboratory of Cardiovascular Receptors Research, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Haihe Laboratory of Cell Ecosystem, Beijing, China (M.Z., N.C., H.G., W.X., K.W., R.G., H.C., X.G., Zijian Li, Y.Z., E.D., H.X.)
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China (W.X., E.D., H.X.)
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Zhu M, Huang Z, Qin J, Jiang J, Fan M. Loss of β-arrestin2 aggravated condylar cartilage degeneration at the early stage of temporomandibular joint osteoarthritis. BMC Musculoskelet Disord 2024; 25:451. [PMID: 38844905 PMCID: PMC11154996 DOI: 10.1186/s12891-024-07558-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 05/29/2024] [Indexed: 06/10/2024] Open
Abstract
OBJECTIVE Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative joint disorder characterized by extracellular matrix degeneration and inflammatory response of condylar cartilage. β-arrestin2 is an important regulator of inflammation response, while its role in TMJOA remains unknown. The objective of this study was to investigate the role of β-arrestin2 in the development of TMJOA at the early stage and the underlying mechanism. METHODS A unilateral anterior crossbite (UAC) model was established on eight-week-old wild-type (WT) and β-arrestin2 deficiency mice to simulate the progression of TMJOA. Hematoxylin-eosin (HE) staining and microcomputed tomography (micro-CT) analysis were used for histological and radiographic assessment. Immunohistochemistry was performed to detect the expression of inflammatory and degradative cytokines, as well as autophagy related factors. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay was carried out to assess chondrocyte apoptosis. RESULTS The loss of β-arrestin2 aggravated cartilage degeneration and subchondral bone destruction in the model of TMJOA at the early stage. Furthermore, in UAC groups, the expressions of degradative (Col-X) and inflammatory (TNF-α and IL-1β) factors in condylar cartilage were increased in β-arrestin2 null mice compared with WT mice. Moreover, the loss of β-arrestin2 promoted apoptosis and autophagic process of chondrocytes at the early stage of TMJOA. CONCLUSION In conclusion, we demonstrated for the first time that β-arrestin2 plays a protective role in the development of TMJOA at the early stage, probably by inhibiting apoptosis and autophagic process of chondrocytes. Therefore, β-arrestin2 might be a potential therapeutic target for TMJOA, providing a new insight for the treatment of TMJOA at the early stage.
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Affiliation(s)
- Mengjiao Zhu
- Department of Orthodontics, Shanghai Xuhui District Dental Center, 500 Fenglin Road, Shanghai, China
| | - Ziwei Huang
- Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Central Road, Nanjing, China
| | - Jing Qin
- Department of Orthodontics, Shanghai Xuhui District Dental Center, 500 Fenglin Road, Shanghai, China
| | - Jiafeng Jiang
- Department of Pediatric Dentistry, Shanghai Xuhui District Dental Center, 500 Fenglin Road, Shanghai, China.
| | - Mingyue Fan
- Department of Orthodontics, Shanghai Xuhui District Dental Center, 500 Fenglin Road, Shanghai, China.
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5
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Wang X, Yang J, Lu C, Hu Y, Xu Z, Wan Q, Zhang M, Shi T, Liu Z, Liu Y. Qifu Yixin Formula Improves Heart Failure by Enhancing β-Arrestin2 Mediated the SUMOylation of SERCA2a. Drug Des Devel Ther 2024; 18:781-799. [PMID: 38500692 PMCID: PMC10946281 DOI: 10.2147/dddt.s446324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/08/2024] [Indexed: 03/20/2024] Open
Abstract
Purpose This study aimed to elucidate the protective mechanism of Traditional Chinese Medicine (TCM) Qifu Yixin formula (QFYXF) to improve heart failure (HF) by promoting β-arrestin2 (β-arr2)-mediated SERCA2a SUMOylation. Materials and Methods The transverse aortic constriction (TAC)-induced HF mice were treated with QFYXF or carvedilol for 8 weeks. β-arr2-KO mice and their littermate wild-type (WT) mice were used as controls. Neonatal rat cardiomyocytes (NRCMs) were used in vitro. Cardiac function was evaluated by echocardiography and serum NT-proBNP. Myocardial hypertrophy and myocardial fibrosis were assessed by histological staining. β-arr2, SERCA2a, SUMO1, PLB and p-PLB expressions were detected by Western blotting, immunofluorescence and immunohistochemistry. SERCA2a SUMOylation was detected by Co-IP. The molecular docking method was used to predict the binding ability of the main active components of QFYXF to β-arr2, SERCA2a, and SUMO1, and the binding degree of SERCA2a to SUMO1 protein. Results The HF model was constructed 8 weeks after TAC. QFYXF ameliorated cardiac function, inhibiting myocardial hypertrophy and fibrosis. QFYXF promoted SERCA2a expression and SERCA2a SUMOylation. Further investigation showed that QFYXF promoted β-arr2 expression, whereas Barbadin (β-arr2 inhibitor) or β-arr2-KO reduced SERCA2a SUMOylation and attenuated the protective effect of QFYXF improved HF. Molecular docking showed that the main active components of QFYXF had good binding activities with β-arr2, SERCA2a, and SUMO1, and SERCA2a had a high binding degree with SUMO1 protein. Conclusion QFYXF improves HF by promoting β-arr2 mediated SERCA2a SUMOylation and increasing SERCA2a expression.
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Affiliation(s)
- Xinting Wang
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Jiahui Yang
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Cheng Lu
- Department of Cardiology, Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China
| | - Yinqin Hu
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Zhaohui Xu
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Qiqi Wan
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Meng Zhang
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Tianyun Shi
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Zhirui Liu
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
| | - Yongming Liu
- Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, People’s Republic of China
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Nibley PC, Shenoy SK. β-adrenergic receptor signaling mediated by β-arrestins and its potential role in heart failure. CURRENT OPINION IN PHYSIOLOGY 2024; 37:100723. [PMID: 38094036 PMCID: PMC10715791 DOI: 10.1016/j.cophys.2023.100723] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2025]
Abstract
The lethality of heart failure (HF), particularly in the context of post-acute sequelae SARS-CoV-2 infection (PASC)-related myocarditis, necessitates the discovery of the cellular pathways implicated in cardiovascular disease (CVD). We summarize the signaling mechanisms of the catecholamine-binding β-adrenergic receptors (β-ARs), with an emphasis on the role of β-arrestins. β-ARs, a subset of G protein-coupled receptors (GPCRs), canonically propagate signals through heterotrimeric G proteins. However, since their discovery in the late 1980s, β-arrestins have been shown to, both (i) quench G protein signaling and (ii) initiate their own independent signaling cascades, which is influenced by post-translational modifications. β-arrestin-biased agonism by the beta-blocker carvedilol and its allosteric modulation can serve a cardioprotective role. The increasingly labyrinthine nature of GPCR signaling suggests that ligand-dependent β-AR signaling, either stimulated by an agonist or blocked by an antagonist, is selectively enhanced or suppressed by allosteric modulations, which are orchestrated by novel drugs or endogenous post-translational modifications.
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Affiliation(s)
- Preston C. Nibley
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
- Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Sudha K. Shenoy
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
- Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
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7
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Yu S, Sun Z, Wang X, Ju T, Wang C, Liu Y, Qu Z, Liu K, Mei Z, Li N, Lu M, Wu F, Huang M, Pang X, Jia Y, Li Y, Zhang Y, Dou S, Jiang J, Li X, Yang B, Du W. Mettl13 protects against cardiac contractile dysfunction by negatively regulating C-Cbl-mediated ubiquitination of SERCA2a in ischemic heart failure. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2786-2804. [PMID: 37450238 DOI: 10.1007/s11427-022-2351-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/14/2023] [Indexed: 07/18/2023]
Abstract
Ischemic heart failure (HF) remains a leading cause of morbidity and mortality. Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression. Methyltransferase-like protein 13 (Mettl13) has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase, but its role in cardiac pathology remains unexplored. This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF. We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction (MI) and in a cellular model of oxidative stress. Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI, while silencing of Mettl13 impaired cardiac function in normal mice. Moreover, Mettl13 overexpression abrogated the reduction in cell shortening, Ca2+ transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI. Conversely, knockdown of Mettl13 impaired the contractility of cardiomyocytes, and decreased Ca2+ transient amplitude and SERCA2a protein expression in vivo and in vitro. Mechanistically, Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl, which in turn inhibited ubiquitination-dependent degradation of SERCA2a. Furthermore, the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca2+ transients were partially rescued by silencing c-Cbl in H2O2-treated cardiomyocytes. In conclusion, our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling, and identifies Mettl13 as a novel therapeutic target for ischemic HF.
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Affiliation(s)
- Shuting Yu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - ZhiYong Sun
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xiuzhu Wang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Tiantian Ju
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Changhao Wang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yingqi Liu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Zhezhe Qu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - KuiWu Liu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Zhongting Mei
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Na Li
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Meixi Lu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Fan Wu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Min Huang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xiaochen Pang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yingqiong Jia
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Ying Li
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yaozhi Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Shunkang Dou
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Jianhao Jiang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xin Li
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Baofeng Yang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150081, China.
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China.
| | - Weijie Du
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150081, China.
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China.
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Guven B, Onay-Besikci A. Past and present of beta arrestins: A new perspective on insulin secretion and effect. Eur J Pharmacol 2023; 956:175952. [PMID: 37541367 DOI: 10.1016/j.ejphar.2023.175952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/24/2023] [Accepted: 08/01/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND Beta arrestins had been known as intracellular adaptors that uncouple and inactivate the G protein-coupled receptors that they interact with. Their roles as signal initiators for some receptors have recently been recognized. SCOPE OF REVIEW In this review, we focused on their role in mediating metabolic modulation primarily in relation to insulin signaling. Commenced by the upstream receptor, they seem to act like intracellular hubs that divert the metabolic profile of the cell. The amount of metabolic substrates in circulation and their usage/deposition by tissues are controlled by the contribution of all systems in the organism. This control is enabled by the release of hormones such as insulin, glucagon and glucagon-like peptide-1. Intriguingly, some ligands -either agonists or antagonists-of different classes of receptors have preferential properties mediated by β arrestins. This is not surprizing considering that substrate supply and usage should parallel physiological function such as hormone release or muscle contraction. MAJOR CONCLUSIONS Available data indicate that β arrestins conduct the regulatory role in insulin secretion and action. They may be good candidates to target when the upstream signal demands the function that may compromise the cell. An example is carvedilol that is protective by preventing the stimulatory effects of excessive catecholamines, stimulates mitochondrial function and has preferential clinical outcomes in metabolic disorders.
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Affiliation(s)
- Berna Guven
- Faculty of Pharmacy, Department of Pharmacology, Ankara University, Ankara, Turkey
| | - Arzu Onay-Besikci
- Faculty of Pharmacy, Department of Pharmacology, Ankara University, Ankara, Turkey.
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9
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Peng S, Wang M, Zhang S, Liu N, Li Q, Kang J, Chen L, Li M, Pang K, Huang J, Lu F, Zhao D, Zhang W. Hydrogen sulfide regulates SERCA2a SUMOylation by S-Sulfhydration of SENP1 to ameliorate cardiac systole-diastole function in diabetic cardiomyopathy. Biomed Pharmacother 2023; 160:114200. [PMID: 36750014 DOI: 10.1016/j.biopha.2022.114200] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/20/2022] [Accepted: 12/30/2022] [Indexed: 02/07/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus that eventually progresses to heart failure. The sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a), an important calcium pump in cardiomyocytes, is closely related to myocardial systolic-diastolic function. In mammalian cells, hydrogen sulfide (H2S), as a second messenger, antioxidant, and sulfurizing agent, is involved in diverse biological processes. Despite the importance of H2S for protection against DCM, the mechanisms remain poorly understood. The aim of the present study was to determine whether H2S regulates intracellular calcium homeostasis by acting on SERCA2a to reduce cardiomyocyte apoptosis during DCM. Db/db mice were injected with NaHS for 18 weeks. Neonatal rat cardiomyocytes (NRCMs) were treated with high glucose, palmitate, oleate, and NaHS for 48 h. Compared to the NaHS-treated groups, in vivo and in vitro type 2 diabetic models both showed reduced intracellular H2S content, reduced cystathionine γ-lyase (CSE) expression, impaired cardiac function, decreased SERCA2a expression and decreased SERCA2a activity, reduced SUMOylation of SERCA2a, increased sentrin-specific protease 1 (SENP1) expression, and disruption of calcium homeostasis leading to activation of the mitochondrial apoptosis pathway. Compared to the NaHS-treated type 2 diabetes cellular model, overexpression of SENP1 C683A reduced the S-sulfhydration of SENP1, reduced the SUMOylation of SERCA2a, reduced the increased expression and activity of SERCA2a, and induced mitochondrial apoptosis in cardiomyocytes. These results suggested that exogenous H2S elevates SENP1 S-sulfhydration to increase SERCA2a SUMOylation, improve myocardial systolic-diastolic function, and decrease cardiomyocyte apoptosis in DCM.
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Affiliation(s)
- Shuo Peng
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Mengyi Wang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Shiwu Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Ning Liu
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Qianzhu Li
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Jiaxin Kang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Lingxue Chen
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Mingyu Li
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Kemiao Pang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Jiayi Huang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Fanghao Lu
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
| | - Dechao Zhao
- Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
| | - Weihua Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
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10
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Chevalier P, Roy P, Bessière F, Morel E, Ankou B, Morgan G, Halder I, London B, Minobe WA, Slavov D, Delinière A, Bochaton T, Paganelli F, Lesavre N, Boiteux C, Mansourati J, Maury P, Clerici G, Winum PF, Huebler SP, Carroll IA, Bristow MR. Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia. J Am Heart Assoc 2023; 12:e025368. [PMID: 36926933 PMCID: PMC10111522 DOI: 10.1161/jaha.122.025368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving β-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and β-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.
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Affiliation(s)
- Philippe Chevalier
- Rhythmology Department Hospital Louis Pradel Lyon France
- Université Claude Bernard Lyon 1 Université de Lyon Lyon France
| | - Pascal Roy
- Hospices Civils de Lyon, Services Biostatistiques Lyon France
| | | | - Elodie Morel
- Rhythmology Department Hospital Louis Pradel Lyon France
| | | | - Gina Morgan
- Division of Cardiovascular Medicine University of Iowa Iowa City IA
| | - Indrani Halder
- Division of Cardiovascular Medicine University of Iowa Iowa City IA
| | - Barry London
- Division of Cardiovascular Medicine University of Iowa Iowa City IA
| | - Wayne A Minobe
- Division of Cardiology University of Colorado Anschutz Medical Campus Aurora CO
| | - Dobromir Slavov
- Division of Cardiology University of Colorado Anschutz Medical Campus Aurora CO
| | | | - Thomas Bochaton
- Department of Intensive Cardiac Care Hospital Louis Pradel Lyon France
| | | | | | | | - Jacques Mansourati
- Cardiology Department Hôpital de La Cavale Blanche, Brest University Hospital Brest France
| | - Philippe Maury
- Cardiology Department University Hospital Rangueil Toulouse France
| | - Gaël Clerici
- Cardiology Department Saint Pierre University Hospital La Réunion France
| | | | | | - Ian A Carroll
- Division of Cardiology University of Colorado Anschutz Medical Campus Aurora CO
- ARCA Biopharma Westminster CO
| | - Michael R Bristow
- Division of Cardiology University of Colorado Anschutz Medical Campus Aurora CO
- ARCA Biopharma Westminster CO
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11
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Yang J, Yan B, Zhang H, Lu Q, Yang L, Liu P, Bai L. Estimating the causal effects of genetically predicted plasma proteome on heart failure. Front Cardiovasc Med 2023; 10:978918. [PMID: 36860279 PMCID: PMC9968807 DOI: 10.3389/fcvm.2023.978918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 01/27/2023] [Indexed: 02/16/2023] Open
Abstract
Background Heart Failure (HF) is the end-stage cardiovascular syndrome with poor prognosis. Proteomics holds great promise in the discovery of novel biomarkers and therapeutic targets for HF. The aim of this study is to investigate the causal effects of genetically predicted plasma proteome on HF using the Mendelian randomization (MR) approach. Methods Summary-level data for the plasma proteome (3,301 healthy individuals) and HF (47,309 cases; 930,014 controls) were extracted from genome-wide association studies (GWASs) of European descent. MR associations were obtained using the inverse variance-weighted (IVW) method, sensitivity analyses, and multivariable MR analyses. Results Using single-nucleotide polymorphisms as instrumental variables, 1-SD increase in MET level was associated with an approximately 10% decreased risk of HF (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.89 to 0.95; p = 1.42 × 10-6), whereas increases in the levels of CD209 (OR: 1.04; 95% CI: 1.02-1.06; p = 6.67 × 10-6) and USP25 (OR: 1.06; 95% CI: 1.03-1.08; p = 7.83 × 10-6) were associated with an increased risk of HF. The causal associations were robust in sensitivity analyses, and no evidence of pleiotropy was observed. Conclusion The study findings suggest that the hepatocyte growth factor/c-MET signaling pathway, dendritic cells-mediated immune processes, and ubiquitin-proteasome system pathway are involved in the pathogenesis of HF. Moreover, the identified proteins have potential to uncover novel therapies for cardiovascular diseases.
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Affiliation(s)
- Jian Yang
- Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
| | - Bin Yan
- Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
| | - Haoxuan Zhang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Qun Lu
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
| | - Lihong Yang
- Clinical Research Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
| | - Ping Liu
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
| | - Ling Bai
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China,*Correspondence: Ling Bai,
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12
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Liu Z, Liu X, Liu L, Wang Y, Zheng J, Li L, Li S, Zhang H, Ni J, Ma C, Gao X, Bian X, Fan G. SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity. J Pharm Anal 2023; 13:170-186. [PMID: 36908856 PMCID: PMC9999303 DOI: 10.1016/j.jpha.2022.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/19/2022] [Accepted: 11/27/2022] [Indexed: 12/11/2022] Open
Abstract
Small ubiquitin-related modifier (SUMOylation) is a dynamic post-translational modification that maintains cardiac function and can protect against a hypertrophic response to cardiac pressure overload. However, the function of SUMOylation after myocardial infarction (MI) and the molecular details of heart cell responses to SUMO1 deficiency have not been determined. In this study, we demonstrated that SUMO1 protein was inconsistently abundant in different cell types and heart regions after MI. However, SUMO1 knockout significantly exacerbated systolic dysfunction and infarct size after myocardial injury. Single-nucleus RNA sequencing revealed the differential role of SUMO1 in regulating heart cells. Among cardiomyocytes, SUMO1 deletion increased the Nppa + Nppb + Ankrd1 + cardiomyocyte subcluster proportion after MI. In addition, the conversion of fibroblasts to myofibroblasts subclusters was inhibited in SUMO1 knockout mice. Importantly, SUMO1 loss promoted proliferation of endothelial cell subsets with the ability to reconstitute neovascularization and expressed angiogenesis-related genes. Computational analysis of ligand/receptor interactions suggested putative pathways that mediate cardiomyocytes to endothelial cell communication in the myocardium. Mice preinjected with cardiomyocyte-specific AAV-SUMO1, but not the endothelial cell-specific form, and exhibited ameliorated cardiac remodeling following MI. Collectively, our results identified the role of SUMO1 in cardiomyocytes, fibroblasts, and endothelial cells after MI. These findings provide new insights into SUMO1 involvement in the pathogenesis of MI and reveal novel therapeutic targets.
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Affiliation(s)
- Zhihao Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Xiaozhi Liu
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Li Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Ying Wang
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Jie Zheng
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Lan Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Sheng Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China
| | - Han Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Jingyu Ni
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Xiumei Gao
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Xiyun Bian
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin, 300450, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.,State Key Laboratory of Component-Based Chinese Medicine, Tianjin, 301617, China.,Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
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13
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Kaur G, Verma SK, Singh D, Singh NK. Role of G-Proteins and GPCRs in Cardiovascular Pathologies. Bioengineering (Basel) 2023; 10:bioengineering10010076. [PMID: 36671648 PMCID: PMC9854459 DOI: 10.3390/bioengineering10010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/19/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Cell signaling is a fundamental process that enables cells to survive under various ecological and environmental contexts and imparts tolerance towards stressful conditions. The basic machinery for cell signaling includes a receptor molecule that senses and receives the signal. The primary form of the signal might be a hormone, light, an antigen, an odorant, a neurotransmitter, etc. Similarly, heterotrimeric G-proteins principally provide communication from the plasma membrane G-protein-coupled receptors (GPCRs) to the inner compartments of the cells to control various biochemical activities. G-protein-coupled signaling regulates different physiological functions in the targeted cell types. This review article discusses G-proteins' signaling and regulation functions and their physiological relevance. In addition, we also elaborate on the role of G-proteins in several cardiovascular diseases, such as myocardial ischemia, hypertension, atherosclerosis, restenosis, stroke, and peripheral artery disease.
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Affiliation(s)
- Geetika Kaur
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
| | - Shailendra Kumar Verma
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
| | - Deepak Singh
- Lloyd Institute of Engineering and Technology, Greater Noida 201306, India
| | - Nikhlesh K. Singh
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
- Correspondence:
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14
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Yan CH, Liu HW, Tian XX, Li J, Ding Y, Li Y, Mei Z, Zou MH, Han YL. AMPKα2 controls the anti-atherosclerotic effects of fish oils by modulating the SUMOylation of GPR120. Nat Commun 2022; 13:7721. [PMID: 36513627 PMCID: PMC9747961 DOI: 10.1038/s41467-022-34996-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 11/15/2022] [Indexed: 12/15/2022] Open
Abstract
Consuming fish oils (FO) is linked to reduced risk of cardiovascular disease in certain populations. However, FO failed to exhibit therapeutic effects in some patients with cardiovascular disease. This study aimed to determine the possible reasons for the inconsistent effects of FO. AMP-activated protein kinase (AMPK) α2 is an important energy metabolic sensor, which was reported to involve in FO mediated regulation of lipid and glucose metabolism. In an in vivo study, FO administration significantly reduced the aortic lesions and inflammation in the Ldlr-/- mouse model of atherosclerosis, but not in Ldlr-/-/Prkaa2-/-and Ldlr-/-/Prkaa2-/-Sm22Cre mice. Mechanistically, inactivation of AMPKα2 increased the SUMOylation of the fatty acid receptor GPR120 to block FO-induced internalization and binding to β-arrestin. In contrast, activation of AMPKα2 can phosphorylate the C-MYC at Serine 67 to inhibit its trans-localization into the nuclei and transcription of SUMO-conjugating E2 enzyme UBC9 and SUMO2/3 in vascular smooth muscle cells (VSMCs), which result in GPR120 SUMOylation. In human arteries, AMPKα2 levels were inversely correlated with UBC9 expression. In a cohort of patients with atherosclerosis, FO concentrations did not correlate with atherosclerotic severity, however, in a subgroup analysis a negative correlation between FO concentrations and atherosclerotic severity was found in patients with higher AMPKα2 levels. These data indicate that AMPKα2 is required for the anti-inflammatory and anti-atherosclerotic effects of FO.
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Affiliation(s)
- Cheng-hui Yan
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Hai-Wei Liu
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Xiao-xiang Tian
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Jiayin Li
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Ye Ding
- grid.256304.60000 0004 1936 7400Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303 USA
| | - Yi Li
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Zhu Mei
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
| | - Ming-Hui Zou
- grid.256304.60000 0004 1936 7400Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303 USA
| | - Ya-ling Han
- Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016 China
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15
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SUMOylation targeting mitophagy in cardiovascular diseases. J Mol Med (Berl) 2022; 100:1511-1538. [PMID: 36163375 DOI: 10.1007/s00109-022-02258-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022]
Abstract
Small ubiquitin-like modifier (SUMO) plays a key regulatory role in cardiovascular diseases, such as cardiac hypertrophy, hypertension, atherosclerosis, and cardiac ischemia-reperfusion injury. As a multifunctional posttranslational modification molecule in eukaryotic cells, SUMOylation is essentially associated with the regulation of mitochondrial dynamics, especially mitophagy, which is involved in the progression and development of cardiovascular diseases. SUMOylation targeting mitochondrial-associated proteins is admittedly considered to regulate mitophagy activation and mitochondrial functions and dynamics, including mitochondrial fusion and fission. SUMOylation triggers mitochondrial fusion to promote mitochondrial dysfunction by modifying Fis1, OPA1, MFN1/2, and DRP1. The interaction between SUMO and DRP1 induces SUMOylation and inhibits lysosomal degradation of DRP1, which is further involved in the regulation of mitochondrial fission. Both SUMOylation and deSUMOylation contribute to the initiation and activation of mitophagy by regulating the conjugation of MFN1/2 SERCA2a, HIF1α, and PINK1. SUMOylation mediated by the SUMO molecule has attracted much attention due to its dual roles in the development of cardiovascular diseases. In this review, we systemically summarize the current understanding underlying the expression, regulation, and structure of SUMO molecules; explore the biochemical functions of SUMOylation in the initiation and activation of mitophagy; discuss the biological roles and mechanisms of SUMOylation in cardiovascular diseases; and further provide a wider explanation of SUMOylation and deSUMOylation research to provide a possible therapeutic strategy for cardiovascular diseases. Considering the precise functions and exact mechanisms of SUMOylation in mitochondrial dysfunction and mitophagy will provide evidence for future experimental research and may serve as an effective approach in the development of novel therapeutic strategies for cardiovascular diseases. Regulation and effect of SUMOylation in cardiovascular diseases via mitophagy. SUMOylation is involved in multiple cardiovascular diseases, including cardiac hypertrophy, hypertension, atherosclerosis, and cardiac ischemia-reperfusion injury. Since it is expressed in multiple cells associated with cardiovascular disease, SUMOylation can be regulated by numerous ligases, including the SENP family proteins PIAS1, PIASy/4, UBC9, and MAPL. SUMOylation regulates the activation and degradation of PINK1, SERCA2a, PPARγ, ERK5, and DRP1 to mediate mitochondrial dynamics, especially mitophagy activation. Mitophagy activation regulated by SUMOylation further promotes or inhibits ventricular diastolic dysfunction, perfusion injury, ventricular remodelling and ventricular noncompaction, which contribute to the development of cardiovascular diseases.
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16
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Xue G, Yang X, Zhan G, Wang X, Gao J, Zhao Y, Wang X, Li J, Pan Z, Xia Y. Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice. Front Pharmacol 2022; 13:988408. [PMID: 36313361 PMCID: PMC9616207 DOI: 10.3389/fphar.2022.988408] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of death. Objective: The purpose of this study was to investigate the influence of empagliflozin (EMPA), an SGLT2 inhibitor, on cardiac electrophysiological remodeling and arrhythmia susceptibility of myocardial infarction mice. Methods: ECG was obtained from mice 1 week after MI to determine the QT interval. In an electrophysiological study and optical mapping was performed to evaluate the function of EMPA and underlying mechanisms of post-myocardial-infarction in mice. Results: EMPA treatment significantly reduced the QT interval of MI mice (MI + EMPA 50.24 ms vs. MI 64.68 ms). The membrane potential and intracellular Ca [Cai] were mapped from 13 MI hearts and five normal hearts using an optical mapping technique. A dynamic pacing protocol was used to determine action potential duration and [Cai] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD80 and CaT80 in normal ventricles while shortening them in an infarct zone, bordering zone, and remote zone of MI hearts at 200 ms, 150 ms, 120 ms, and 100 ms pacing cycle length. The conduction velocity of infarcted ventricles was 0.278 m/s and 0.533 m/s in normal ventricles at baseline (p < 0.05). After EMPA administration, the conduction velocity of infarcted ventricles increased to 0.363 m/s, whereas no significant changes were observed in normal ventricles. The action potential rise time, CaT rise time, and CaT tau time were improved after EMPA perfusion in infarcted ventricles, whereas no significant changes were observed in normal ventricles. EMPA decreases early afterdepolarizations premature ventricular beats, and ventricular fibrillation (VF) in infarcted ventricles. The number of phase singularities (baseline versus EMPA, 6.26 versus 3.25), dominant frequency (20.52 versus 10.675 Hz), and ventricular fibrillation duration (1.072 versus 0.361 s) during ventricular fibrillation in infarcted ventricles were all significantly decreased by EMPA. Conclusion: Treatment with EMPA improved post-MI electrophysiological remodeling and decreased substrate for VF of MI mice. The inhibitors of SGLT2 may be a new class of agents for the prevention of ventricle arrhythmia after chronic MI.
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Affiliation(s)
- Genlong Xue
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaolei Yang
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ge Zhan
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xin Wang
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Ultrasound, The Affiliated Hospital of Innermongolia Medical University, Huhhot, China
| | - Jinghan Gao
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yong Zhao
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xinying Wang
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiatian Li
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhenwei Pan
- Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China
- *Correspondence: Yunlong Xia, ; Zhenwei Pan,
| | - Yunlong Xia
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Yunlong Xia, ; Zhenwei Pan,
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17
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Liu Y, Song N, Yao H, Jiang S, Wang Y, Zheng Y, Zhou Y, Ding J, Hu G, Lu M. β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression. J Neuroinflammation 2022; 19:240. [PMID: 36183107 PMCID: PMC9526944 DOI: 10.1186/s12974-022-02597-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 09/13/2022] [Indexed: 12/17/2022] Open
Abstract
Background Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. Methods We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. Results Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. Conclusions Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02597-6.
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Affiliation(s)
- Yang Liu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nanshan Song
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hang Yao
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Siyuan Jiang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Yueping Wang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Ying Zheng
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuanzhang Zhou
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Jianhua Ding
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Gang Hu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.
| | - Ming Lu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. .,Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China.
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18
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Maning J, Desimine VL, Pollard CM, Ghandour J, Lymperopoulos A. Carvedilol Selectively Stimulates βArrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility. Int J Mol Sci 2022; 23:11315. [PMID: 36232617 PMCID: PMC9570329 DOI: 10.3390/ijms231911315] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/09/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β1AR-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain β-blockers, such as carvedilol and metoprolol, can activate βarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac βarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces βarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the β2AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied β2AR subtype on carvedilol-occupied β1AR-stimulated, βarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress βarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs' shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing βarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates βarrestin2-mediated SERCA2a SUMOylation and activity through the β1AR in cardiac myocytes, translating into direct positive inotropy. However, this unique βarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound β2AR subtype signaling.
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Affiliation(s)
| | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA
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Jiang H, Galtes D, Wang J, Rockman HA. G protein-coupled receptor signaling: transducers and effectors. Am J Physiol Cell Physiol 2022; 323:C731-C748. [PMID: 35816644 PMCID: PMC9448338 DOI: 10.1152/ajpcell.00210.2022] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/27/2022] [Accepted: 07/10/2022] [Indexed: 01/14/2023]
Abstract
G protein-coupled receptors (GPCRs) are of considerable interest due to their importance in a wide range of physiological functions and in a large number of Food and Drug Administration (FDA)-approved drugs as therapeutic entities. With continued study of their function and mechanism of action, there is a greater understanding of how effector molecules interact with a receptor to initiate downstream effector signaling. This review aims to explore the signaling pathways, dynamic structures, and physiological relevance in the cardiovascular system of the three most important GPCR signaling effectors: heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. We will first summarize their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. As new technologies are developed and applied to studying GPCR structure and their downstream effectors, there is increasing appreciation for the elegance of the regulatory mechanisms that mediate intracellular signaling and function.
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Affiliation(s)
- Haoran Jiang
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Daniella Galtes
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Jialu Wang
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Howard A Rockman
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina
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Borges JI, Ferraino KE, Cora N, Nagliya D, Suster MS, Carbone AM, Lymperopoulos A. Adrenal G Protein-Coupled Receptors and the Failing Heart: A Long-distance, Yet Intimate Affair. J Cardiovasc Pharmacol 2022; 80:386-392. [PMID: 34983911 PMCID: PMC9294064 DOI: 10.1097/fjc.0000000000001213] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/11/2021] [Indexed: 01/31/2023]
Abstract
Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT 1 Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland.
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Affiliation(s)
- Jordana I. Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Krysten E. Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Deepika Nagliya
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Malka S. Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Alexandra M. Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
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21
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Carbone AM, Borges JI, Suster MS, Sizova A, Cora N, Desimine VL, Lymperopoulos A. Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling. Int J Mol Sci 2022; 23:5803. [PMID: 35628613 PMCID: PMC9147283 DOI: 10.3390/ijms23105803] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/16/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open
Abstract
Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate's actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.
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Affiliation(s)
| | | | | | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA; (A.M.C.); (J.I.B.); (M.S.S.); (A.S.); (N.C.); (V.L.D.)
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22
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Pollard CM, Suster MS, Cora N, Carbone AM, Lymperopoulos A. GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone. World J Cardiol 2022; 14:220-230. [PMID: 35582468 PMCID: PMC9048278 DOI: 10.4330/wjc.v14.i4.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/17/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. METHODS We used H9c2 cardiomyocytes, which endogenously express the MR and GRK5. RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone's inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally, GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis, oxidative stress, and fibrosis. CONCLUSION Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.
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Affiliation(s)
- Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Malka S Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States.
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Lashen SA, Shamseya MM, Madkour MA, Abdel Salam RM, Mostafa SS. β-arrestin-2 predicts the clinical response to β-blockers in cirrhotic portal hypertension patients: A prospective study. World J Hepatol 2022; 14:429-441. [PMID: 35317175 PMCID: PMC8891671 DOI: 10.4254/wjh.v14.i2.429] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/08/2022] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Portal hypertension, a common complication associated with liver cirrhosis, can result in variceal bleeding, which greatly impacts patient survival. Recently, β-arrestin-2 has been shown to predict the acute hemodynamic response to nonselective β-blocker therapy for cirrhotic portal hypertension. However, more data is needed on the long-term effects of and changes in β-arrestin-2 following nonselective β-blocker therapy. AIM To investigate the expression and role of β-Arrestin-2 in predicting the long-term response to nonselective β-blockers in cirrhotic portal hypertensive patients. METHODS We prospectively enrolled 91 treatment-naïve patients with cirrhotic portal hypertension. Baseline clinical and laboratory data were obtained. Gastroscopy was performed for grading and treating varices and obtaining gastric antral biopsies. We measured the serum and antral expression of β-arrestin-2 and obtained Doppler measurement of the portal vein congestion index. Treatment with nonselective β-blockers was then started. The patients were followed up for 18 mo, after which they have undergone a repeat antral biopsy and re-evaluation of the portal vein congestion index. RESULTS A higher serum level and antral expression of β-arrestin-2 was associated with longer bleeding-free intervals, greater reduction in the portal vein congestion index, and improved grade of varices. Among patients with a low β-arrestin-2 expression, 17.6% were nonselective β-blocker responders, whereas, among those with high expression, 95.1% were responders (P < 0.001). A serum β-arrestin-2 value ≥ 2.23 ng/mL was associated with a lower likelihood of variceal bleeding (90% sensitivity and 71% specificity). β-arrestin-2 expression significantly decreased after nonselective β-blocker therapy. CONCLUSION β-arrestin-2 expression in cirrhotic portal hypertension predicts the clinical response to long-term nonselective β-blocker treatment. Serum β-arrestin-2 is a potential noninvasive biomarker for selecting the candidate patients for nonselective β-blockers.
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Affiliation(s)
- Sameh A Lashen
- Division of Hepatology and Gastroenterology, Faculty of Medicine, Alexandria University, Alexandria 21521, Egypt.
| | - Mohammed M Shamseya
- Department of Experimental and Clinical Internal Medicine, Medical Research Institute, Alexandria 21561, Egypt
| | - Marwa A Madkour
- Department of Experimental and Clinical Internal Medicine, Medical Research Institute, Alexandria 21561, Egypt
| | - Radwa M Abdel Salam
- Department of Pathology, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt
| | - Sanaa S Mostafa
- Department of Pathology, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt
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24
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Mohamed RMSM, Elshazly SM, Mahmoud NM. Amlexanox Exhibits Cardioprotective Effects in 5/6 Nephrectomized Rats. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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25
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Lino CA, Barreto-Chaves ML. Beta-arrestins in the context of cardiovascular diseases: Focusing on type 1 angiotensin II receptor (AT1R). Cell Signal 2022; 92:110253. [DOI: 10.1016/j.cellsig.2022.110253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/16/2022]
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26
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Borges JI, Carbone AM, Cora N, Sizova A, Lymperopoulos A. GTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic Alpha 2B-Adrenoceptor Variants. Methods Mol Biol 2022; 2547:267-273. [PMID: 36068469 DOI: 10.1007/978-1-0716-2573-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
α2-Adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine, including inhibition of their secretion (sympathetic inhibition) from adrenal chromaffin cells. Like many other G protein-coupled receptors (GPCRs), they undergo agonist-dependent phosphorylation and desensitization by GPCR kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A three-glutamic acid deletion polymorphism in the human α2B-AR subtype gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in adrenal chromaffin cells. One of the various pharmacological assays that can be used to quantify and quantitatively compare the degrees of agonist-dependent desensitization, i.e., G protein decoupling, of these two polymorphic α2B-AR variants (or of any two GPCRs for that matter) is the guanosine-5'-O-3-thiotriphosphate (GTPγS) assay that can directly quantify heterotrimeric G protein activation.
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Affiliation(s)
- Jordana I Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA.
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27
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Ibrahim WS, Ahmed HMS, Mahmoud AAA, Mahmoud MF, Ibrahim IAAEH. Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance β-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin. Life Sci 2021; 286:120055. [PMID: 34662551 DOI: 10.1016/j.lfs.2021.120055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 01/14/2023]
Abstract
AIMS β-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate β-arrestin2 signaling. The current study examined the effects of the β-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. MATERIALS AND METHODS Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic β-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling were then compared among groups. KEY FINDINGS HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic β-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced β-arrestin2 signaling with variable efficacies. SIGNIFICANCE Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating β-arrestin2 signaling activity. Therefore, β-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.
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Affiliation(s)
- Wael S Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Department of Pharmacology, School of Pharmacy, Badr University in Cairo, Cairo, Egypt
| | - Hoda M S Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Medical Supply Chain, Abo-Hammad Health Administration, Ministry of Health, Egypt
| | - Amr A A Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Islam A A E-H Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt.
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28
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Lymperopoulos A, Borges JI, Carbone AM, Cora N, Sizova A. Cardiovascular angiotensin II type 1 receptor biased signaling: Focus on non-Gq-, non-βarrestin-dependent signaling. Pharmacol Res 2021; 174:105943. [PMID: 34662735 DOI: 10.1016/j.phrs.2021.105943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
The physiological and pathophysiological roles of the angiotensin II type 1 (AT1) receptor, a G protein-coupled receptor ubiquitously expressed throughout the cardiovascular system, have been the focus of intense investigations for decades. The success of angiotensin converting enzyme inhibitors (ACEIs) and of angiotensin receptor blockers (ARBs), which are AT1R-selective antagonists/inverse agonists, in the treatment of heart disease is a testament to the importance of this receptor for cardiovascular homeostasis. Given the pleiotropic signaling of the cardiovascular AT1R and, in an effort to develop yet better drugs for heart disease, the concept of biased signaling has been exploited to design and develop biased AT1R ligands that selectively activate β-arrestin transduction pathways over Gq protein-dependent pathways. However, by focusing solely on Gq or β-arrestins, studies on AT1R "biased" signaling & agonism tend to largely ignore other non-Gq-, non β-arrestin-dependent signaling modalities the very versatile AT1R employs in cardiovascular tissues, including two very important types of signal transducers/regulators: other G protein types (e.g., Gi/o, G12/13) & the Regulator of G protein Signaling (RGS) proteins. In this review, we provide a brief overview of the current state of cardiovascular AT1R biased signaling field with a special focus on the non-Gq-, non β-arrestin-dependent signaling avenues of this receptor in the cardiovascular system, which usually get left out of the conversation of "biased" AT1R signal transduction.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
| | - Jordana I Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
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29
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Mohamed RMSM, Elshazly SM, Nafea OE, Abd El Motteleb DM. Comparative cardioprotective effects of carvedilol versus atenolol in a rat model of cardiorenal syndrome type 4. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:2117-2128. [PMID: 34398250 DOI: 10.1007/s00210-021-02130-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 07/28/2021] [Indexed: 12/23/2022]
Abstract
The incidence of chronic kidney disease is escalating; cardiorenal syndrome (CRS) type 4 is gaining a major health concern causing significant morbidity and mortality, putting major burdens on the healthcare system. This study was designed to compare the cardioprotective effects of carvedilol versus atenolol against CRS type 4 induced by subtotal 5/6 nephrectomy in rats and to explore the underlying mechanisms. Immediately after surgery, carvedilol (20 mg/kg/day) or atenolol (20 mg/kg/day) was added to drinking water for 10 weeks. Carvedilol was more effective than atenolol in improving kidney functions, decreasing elevated blood pressures, attenuating cardiac hypertrophy, reducing serum brain natriuretic peptide, and diminished cardiac fibrous tissue deposition. However, carvedilol was equivalent to atenolol in modulating β1-adrenergic receptors (β1ARs) and cardiac diacylglycerol (DAG) signaling, but carvedilol was superior in modulating β-arrestin2, phosphatidyl inositol 4,5 bisphosphates (PIP2), and caspase 3 levels. Carvedilol has superior cardioprotective effects than atenolol in a rat model of CRS type 4. These protective effects are mediated through modulating cardiac β1ARs/β-arrestin2/PIP2/DAG as well as abating cardiac apoptotic signaling pathways (caspase3/pS473 protein kinase B (Akt)).
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Affiliation(s)
- Rasha M S M Mohamed
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Shimaa M Elshazly
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Ola E Nafea
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia.
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Du X. Sympatho-adrenergic mechanisms in heart failure: new insights into pathophysiology. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:47-77. [PMID: 37724075 PMCID: PMC10388789 DOI: 10.1515/mr-2021-0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/02/2021] [Indexed: 09/20/2023]
Abstract
The sympathetic nervous system is activated in the setting of heart failure (HF) to compensate for hemodynamic instability. However, acute sympathetic surge or sustained high neuronal firing rates activates β-adrenergic receptor (βAR) signaling contributing to myocardial remodeling, dysfunction and electrical instability. Thus, sympatho-βAR activation is regarded as a hallmark of HF and forms pathophysiological basis for β-blocking therapy. Building upon earlier research findings, studies conducted in the recent decades have significantly advanced our understanding on the sympatho-adrenergic mechanism in HF, which forms the focus of this article. This review notes recent research progress regarding the roles of cardiac β2AR or α1AR in the failing heart, significance of β1AR-autoantibodies, and βAR signaling through G-protein independent signaling pathways. Sympatho-βAR regulation of immune cells or fibroblasts is specifically discussed. On the neuronal aspects, knowledge is assembled on the remodeling of sympathetic nerves of the failing heart, regulation by presynaptic α2AR of NE release, and findings on device-based neuromodulation of the sympathetic nervous system. The review ends with highlighting areas where significant knowledge gaps exist but hold promise for new breakthroughs.
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Affiliation(s)
- Xiaojun Du
- Faculty of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an710061, Shaanxi, China
- Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC3004, Australia
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31
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Liu Z, Bian X, Gao W, Su J, Ma C, Xiao X, Yu T, Zhang H, Liu X, Fan G. Rg3 promotes the SUMOylation of SERCA2a and corrects cardiac dysfunction in heart failure. Pharmacol Res 2021; 172:105843. [PMID: 34428586 DOI: 10.1016/j.phrs.2021.105843] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/08/2021] [Accepted: 08/18/2021] [Indexed: 01/14/2023]
Abstract
SUMOylation of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) has been shown to play a critical role in the abnormal Ca2+ cycle of heart failure. Ginsenoside Rg3 (Rg3), the main active constituent of Panax ginseng, exerts a wide range of pharmacological effects in cardiovascular diseases. However, the effect of Rg3 on abnormal Ca2+ homeostasis in heart failure has not been reported. In this study, we showed a novel role of Rg3 in the abnormal Ca2+ cycle in cardiomyocytes of mice with heart failure. Among mice undergoing transverse aortic constriction, animals that received Rg3 showed improvements in cardiac function and Ca2+ homeostasis, accompanied by increases in the SUMOylation level and SERCA2a activity. In an isoproterenol (ISO)-induced cell hypertrophy model, Rg3 reduced the ISO-induced Ca2+ overload in HL-1 cells. Gene knockout of SUMO1 in mice inhibited the cardioprotective effect of Rg3, and SUMO1 knockout mice that received Rg3 did not exhibit improved Ca2+ homeostasis in cardiomyocytes. Additionally, mutation of the SUMOylation sites of SERCA2a blocked the positive effect of Rg3 on the ISO-induced abnormal Ca2+ cycle in HL-1 cells, and was accompanied by an abnormal endoplasmic reticulum stress response and generation of ROS. Our data demonstrated that Rg3 has a positive effect on the abnormal Ca2+ cycle in the cardiomyocytes of mice with heart failure. SUMO1 is an important factor that mediates the protective effect of Rg3. Our findings suggest that drug intervention by regulating the SUMOylation of SERCA2a can provide a novel therapeutic strategy for the treatment of heart failure.
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Affiliation(s)
- Zhihao Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiyun Bian
- Central Laboratory, the Fifth Central Hospital of Tianjin, Tianjin 300450, China; Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, the Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Wenbo Gao
- Central Laboratory, the Fifth Central Hospital of Tianjin, Tianjin 300450, China; Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, the Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Jing Su
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China
| | - Xiaolin Xiao
- Central Laboratory, the Fifth Central Hospital of Tianjin, Tianjin 300450, China; Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, the Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Tian Yu
- Central Laboratory, the Fifth Central Hospital of Tianjin, Tianjin 300450, China; Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, the Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Han Zhang
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiaozhi Liu
- Central Laboratory, the Fifth Central Hospital of Tianjin, Tianjin 300450, China; Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, the Fifth Central Hospital of Tianjin, Tianjin 300450, China.
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Wright PT, Gorelik J, Harding SE. Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors. Cells 2021; 10:cells10092456. [PMID: 34572106 PMCID: PMC8468945 DOI: 10.3390/cells10092456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 01/09/2023] Open
Abstract
Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.
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Affiliation(s)
- Peter T. Wright
- School of Life & Health Sciences, University of Roehampton, Holybourne Avenue, London SW15 4JD, UK;
- Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK;
| | - Julia Gorelik
- Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK;
| | - Sian E. Harding
- Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK;
- Correspondence:
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Capote AE, Batra A, Warren CM, Chowdhury SAK, Wolska BM, Solaro RJ, Rosas PC. B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging. Front Physiol 2021; 12:696852. [PMID: 34512376 PMCID: PMC8430342 DOI: 10.3389/fphys.2021.696852] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022] Open
Abstract
Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12-16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.
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Affiliation(s)
- Andrielle E. Capote
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - Ashley Batra
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - Chad M. Warren
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - Shamim A. K. Chowdhury
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - Beata M. Wolska
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
- Department of Medicine, Division of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - R. John Solaro
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
| | - Paola C. Rosas
- Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, United States
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Delaitre C, Boisbrun M, Lecat S, Dupuis F. Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes. Int J Mol Sci 2021; 22:ijms22136738. [PMID: 34201646 PMCID: PMC8269339 DOI: 10.3390/ijms22136738] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/17/2021] [Accepted: 06/20/2021] [Indexed: 12/20/2022] Open
Abstract
The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the β-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.
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Affiliation(s)
- Céline Delaitre
- CITHEFOR, Université de Lorraine, F-54000 Nancy, France;
- Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS/Université de Strasbourg, 300 Boulevard Sébastien Brant, CS 10413, CEDEX, 67412 Illkirch-Graffenstaden, France;
| | | | - Sandra Lecat
- Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS/Université de Strasbourg, 300 Boulevard Sébastien Brant, CS 10413, CEDEX, 67412 Illkirch-Graffenstaden, France;
| | - François Dupuis
- CITHEFOR, Université de Lorraine, F-54000 Nancy, France;
- Correspondence: ; Tel.: +33-372747272
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Guitart-Mampel M, Urquiza P, Borges JI, Lymperopoulos A, Solesio ME. Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function. Cells 2021; 10:1552. [PMID: 34205363 PMCID: PMC8235589 DOI: 10.3390/cells10061552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)-particularly βARs-play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.
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Affiliation(s)
- Mariona Guitart-Mampel
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Pedro Urquiza
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Jordana I. Borges
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Maria E. Solesio
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
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Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review. Pharmaceutics 2021. [DOI: 10.3390/pharmaceutics13060838
expr 929824082 + 956151497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors’ (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.
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Rakib A, Eva TA, Sami SA, Mitra S, Nafiz IH, Das A, Tareq AM, Nainu F, Dhama K, Emran TB, Simal-Gandara J. Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review. Pharmaceutics 2021; 13:838. [PMID: 34198801 PMCID: PMC8228839 DOI: 10.3390/pharmaceutics13060838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022] Open
Abstract
Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors' (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.
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Affiliation(s)
- Ahmed Rakib
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Taslima Akter Eva
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Saad Ahmed Sami
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh;
| | - Iqbal Hossain Nafiz
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (I.H.N.); (A.D.)
| | - Ayan Das
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (I.H.N.); (A.D.)
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh;
| | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Kota Makassar, Sulawesi Selatan 90245, Indonesia;
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo–Ourense Campus, E32004 Ourense, Spain
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Ferraino KE, Cora N, Pollard CM, Sizova A, Maning J, Lymperopoulos A. Adrenal angiotensin II type 1 receptor biased signaling: The case for "biased" inverse agonism for effective aldosterone suppression. Cell Signal 2021; 82:109967. [PMID: 33640432 DOI: 10.1016/j.cellsig.2021.109967] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/04/2021] [Accepted: 02/23/2021] [Indexed: 12/21/2022]
Abstract
Angiotensin II (AngII) uses two distinct G protein-coupled receptor (GPCR) types, AT1R and AT2R, to exert a plethora of physiologic effects in the body and to significantly affect cardiovascular homeostasis. Although not much is known about the signaling of the AT2R, AT1R signaling is known to be quite pleiotropic, mobilizing a variety of signal transducers inside cells to produce a biological outcome. When the outcome in question is aldosterone production from the adrenal cortex, the main transducers activated specifically by the adrenocortical AT1R to signal toward that cellular effect are the Gq/11 protein alpha subunits and the β-arrestins (also known as Arrestin-2 and -3). The existence of various downstream pathways the AT1R signal can travel down on has led to the ever-expanding filed of GPCR pharmacology termed "biased" signaling, which refers to a ligand preferentially activating one signaling pathway over others downstream of the same receptor in the same cell. However, "biased" signaling or "biased" agonism is therapeutically desirable only when the downstream pathways lead to different or opposite cellular outcomes, so the pathway promoting the beneficial effect can be selectively activated over the pathway that leads to detrimental consequences. In the case of the adrenal AT1R, both Gq/11 proteins and β-arrestins mediate signaling to the same end-result: aldosterone synthesis and secretion. Therefore, both pathways need to remain inactive in the adrenal cortex to fully suppress the production of aldosterone, which is one of the culprit hormones elevated in chronic heart failure, hypertension, and various other cardiovascular diseases. Variations in the effectiveness of the AT1R antagonists, which constitute the angiotensin receptor blocker (ARB) class of drugs (also known as sartans), at the relative blockade of these two pathways downstream of the adrenal AT1R opens the door to the flip term "biased" inverse agonism at the AT1R. ARBs that are unbiased and equipotent inverse agonists for both G proteins and β-arrestins at this receptor, like candesartan and valsartan, are the most preferred agents with the best efficacy at reducing circulating aldosterone, thereby ameliorating heart failure. In the present review, the biased signaling of the adrenal AT1R, particularly in relation to aldosterone production, is examined and the term "biased" inverse agonism at the AT1R is introduced and explained, as a means of pharmacological categorization of the various agents within the ARB drug class.
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Affiliation(s)
- Krysten E Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
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Lymperopoulos A, Cora N, Maning J, Brill AR, Sizova A. Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe. FEBS J 2021; 288:2645-2659. [PMID: 33599081 DOI: 10.1111/febs.15771] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/02/2021] [Accepted: 02/16/2021] [Indexed: 12/16/2022]
Abstract
The two branches of the autonomic nervous system (ANS), adrenergic and cholinergic, exert a multitude of effects on the human myocardium thanks to the activation of distinct G protein-coupled receptors (GPCRs) expressed on the plasma membranes of cardiac myocytes, cardiac fibroblasts, and coronary vascular endothelial cells. Norepinephrine (NE)/epinephrine (Epi) and acetylcholine (ACh) are released from cardiac ANS terminals and mediate the biological actions of the ANS on the heart via stimulation of cardiac adrenergic or muscarinic receptors, respectively. In addition, several other neurotransmitters/hormones act as facilitators of ANS neurotransmission in the heart, taking part in the so-called nonadrenergic noncholinergic (NANC) part of the ANS's control of cardiac function. These NANC mediators also use several different cell membrane-residing GPCRs to exert their effects in the myocardium. Cardiac ANS dysfunction and an imbalance between the activities of its two branches underlie a variety of cardiovascular diseases, from heart failure and hypertension to coronary artery disease, myocardial ischemia, and arrhythmias. In this review, we present the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and we also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type-specific cardiac effects of each of these autonomic receptors.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Ava R Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
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Haege ER, Huang HC, Huang CC. Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model. Pharmaceuticals (Basel) 2021; 14:ph14030261. [PMID: 33803943 PMCID: PMC7999541 DOI: 10.3390/ph14030261] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022] Open
Abstract
Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which results in quick symptom relief but still poor prognostic outcome. This study utilizes a zebrafish AHF model induced by aristolochic acid (AA) to look for natural products that could attenuate the progression of AHF. The project started off by testing nearly seventy herbal crude extracts. Two of the positive extracts were from Chinese water chestnuts and are further studied in this report. After several rounds of chromatographical chemical fractionation and biological tests, a near pure fraction, named A2-4-2-4, with several hydrophilic compounds was found to attenuate the AA-induced AHF. A2-4-2-4 appeared to inhibit inflammation and cardiac hypertrophy by reducing MAPK signaling activity. Chemical analyses revealed that the major compound in A2-4-2-4 is actually lactate. Pure sodium lactate showed attenuation of the AA-induced AHF and inflammation and cardiac hypertrophy suppression as well, suggesting that the AHF attenuation ability in A2-4-2-4 is attributable to lactate. Our studies identify lactate as a cardiac protectant and a new therapeutic agent for AHF.
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Affiliation(s)
- Elijah R. Haege
- Biology Department, University of Wisconsin-River Falls, River Falls, WI 54022, USA;
| | - Hui-Chi Huang
- Department of Chinese Pharmaceutical Sciences and Chines Medicine Resources, China Medical University, Taichung 40402, Taiwan
- Master Program for Food and Drug Safety, China Medical University, Taichung 40402, Taiwan
- Correspondence: (H.-C.H.); (C.-c.H.); Tel.: +886-4-2205-3366 (ext. 5211) (H.-C.H.); +1-715-425-4276 (C.-c.H.); Fax: +1-715-425-0378 (C.-c.H.)
| | - Cheng-chen Huang
- Biology Department, University of Wisconsin-River Falls, River Falls, WI 54022, USA;
- Correspondence: (H.-C.H.); (C.-c.H.); Tel.: +886-4-2205-3366 (ext. 5211) (H.-C.H.); +1-715-425-4276 (C.-c.H.); Fax: +1-715-425-0378 (C.-c.H.)
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Wang S, Zhou Y, Luo Y, Kan R, Chen J, Xuan H, Wang C, Chen J, Xu T, Li D. SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway to improve cardiac function in myocardial ischemia/reperfusion mice. Sci Rep 2021; 11:2037. [PMID: 33479390 PMCID: PMC7820433 DOI: 10.1038/s41598-021-81570-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 01/07/2021] [Indexed: 12/21/2022] Open
Abstract
Transverse-tubules (T-tubules) play pivotal roles in Ca2+-induced, Ca2+ release and excitation–contraction coupling in cardiomyocytes. The purpose of this study was to uncover mechanisms where sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) improved cardiac function through T-tubule regulation during myocardial ischemia/reperfusion (I/R). SERCA2a protein expression, cytoplasmic [Ca2+]i, calpain activity, junctophilin-2 (JPH2) protein expression and intracellular localization, cardiomyocyte T-tubules, contractility and calcium transients in single cardiomyocytes and in vivo cardiac functions were all examined after SERCA2a knockout and overexpression, and Calpain inhibitor PD150606 (PD) pretreatment, following myocardial I/R. This comprehensive approach was adopted to clarify SERCA2a mechanisms in improving cardiac function in mice. Calpain was activated during myocardial I/R, and led to the proteolytic cleavage of JPH2. This altered the T-tubule network, the contraction function/calcium transients in cardiomyocytes and in vivo cardiac functions. During myocardial I/R, PD pretreatment upregulated JPH2 expression and restored it to its intracellular location, repaired the T-tubule network, and contraction function/calcium transients of cardiomyocytes and cardiac functions in vivo. SERCA2a suppressed calpain activity via [Ca2+]i, and ameliorated these key indices. Our results suggest that SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway, thereby improving cardiac function in myocardial I/R mice.
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Affiliation(s)
- Shuai Wang
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - You Zhou
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Yuanyuan Luo
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Rongsheng Kan
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Jingwen Chen
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Haochen Xuan
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Chaofan Wang
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Junhong Chen
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Tongda Xu
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China.
| | - Dongye Li
- Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China. .,Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, People's Republic of China.
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Abstract
Heart failure is a major source of morbidity and mortality, driven, in part, by maladaptive sympathetic hyperactivity in response to poor cardiac output. Current therapies target β-adrenergic and angiotensin II G protein-coupled receptors to reduce adverse cardiac remodeling and improve clinical outcomes; however, there is a pressing need for new therapeutic approaches to preserve cardiac function. β-arrestin is a multifunctional protein which has come under analysis in recent years as a key player in G protein-coupled receptor signal transduction and a potential therapeutic target in heart failure. β-arrestin attenuates β-adrenergic and angiotensin II receptor signaling to limit the deleterious response to excessive sympathetic stimulation while simultaneously transactivating cardioprotective signaling cascades that preserve cardiac structure and function in response to injury. β-arrestin signaling may provide unique advantages compared to classic heart failure treatment approaches, but a number of challenges currently limit clinical applications. In this review, we discuss the role and functions of β-arrestin and the current attempts to develop G protein-coupled receptor agonists biased towards β-arrestin activation. Furthermore, we examine the functional diversity of cardiac β-arrestin isotypes to explore key considerations in the promise of β-arrestin as a pharmacotherapeutic target in heart failure.
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Manolis AS, Manolis AA, Manolis TA, Apostolaki NE, Apostolopoulos EJ, Melita H, Katsiki N. Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications. Med Res Rev 2020; 41:275-313. [PMID: 32959403 DOI: 10.1002/med.21732] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/04/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022]
Abstract
Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high-efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive-oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria-targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.
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Affiliation(s)
- Antonis S Manolis
- First Department of Cardiology, Athens University School of Medicine, Athens, Greece
| | | | | | | | | | | | - Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece
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Nagi K, Kaur S, Bai Y, Shenoy SK. In-frame fusion of SUMO1 enhances βarrestin2's association with activated GPCRs as well as with nuclear pore complexes. Cell Signal 2020; 75:109759. [PMID: 32860951 DOI: 10.1016/j.cellsig.2020.109759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 08/17/2020] [Accepted: 08/22/2020] [Indexed: 01/11/2023]
Abstract
Small ubiquitin like modifier (SUMO) conjugation or SUMOylation of βarrestin2 promotes its association with the clathrin adaptor protein AP2 and facilitates rapid β2 adrenergic receptor (β2AR) internalization. However, disruption of the consensus SUMOylation site in βarrestin2, did not prevent βarrestin2's association with activated β2ARs, dopamine D2 receptors (D2Rs), angiotensin type 1a receptors (AT1aRs) and V2 vasopressin receptors (V2Rs). To address the role of SUMOylation in the trafficking of βarrestin and GPCR complexes, we generated and characterized a yellow fluorescent protein (YFP) tagged βarrestin2-SUMO1 chimeric protein, which is resistant to de-SUMOylation. In HEK-293 cells, YFP-SUMO1 predominantly localized in the nucleus, whereas YFP-βarrestin2 is cytoplasmic. YFP-βarrestin2-SUMO1 in addition to being cytoplasmic, is localized at the nuclear membrane. Nonetheless, βarrestin2-SUMO1 associated robustly with agonist-activated β2ARs as evaluated by co-immunoprecipitation, confocal microscopy and bioluminescence resonance energy transfer (BRET). βarrestin2-SUMO1 associated strongly with the D2R, which forms transient complexes with βarrestin2. But, βarrestin2-SUMO1 and βarrestin2 showed equivalent binding with the V2R, which forms stable complexes with βarrestin2. βarrestin2 expression level directly correlated with the steady state levels of the unmodified form of RanGAP1, which upon SUMOylation associates with nuclear membrane. On the other hand, βarrestin2-SUMO1 not only localized at the nuclear membrane, but also formed a macromolecular complex with RanGAP1. Taken together, our data suggest that SUMOylation of βarrestin2 promotes its protein interactions at both cell and nuclear membranes. Furthermore, βarrestin2-SUMO1 presents as a useful tool to characterize βarrestin2 recruitment to GPCRs, which form transient and unstable complex with βarrestin2.
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Affiliation(s)
- Karim Nagi
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA; College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Suneet Kaur
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Yushi Bai
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Sudha K Shenoy
- Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
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Wacker C, Dams N, Schauer A, Ritzer A, Volk T, Wagner M. Region-specific mechanisms of corticosteroid-mediated inotropy in rat cardiomyocytes. Sci Rep 2020; 10:11604. [PMID: 32665640 PMCID: PMC7360564 DOI: 10.1038/s41598-020-68308-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/23/2020] [Indexed: 11/09/2022] Open
Abstract
Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction. Corticosteroids such as aldosterone or corticosterone increase the L-type Ca2+ current (ICaL) in the heart via the mineralocorticoid receptor (MR). Here, we investigate the differential impact of corticosteroid-mediated increase in ICaL on action potentials (AP), ion currents, intracellular Ca2+ handling and contractility in endo- and epicardial myocytes of the rat left ventricle. Dexamethasone led to a similar increase in ICaL in endocardial and epicardial myocytes, while the K+ currents Ito and IK were unaffected. However, AP duration (APD) and AP-induced Ca2+ influx (QCa) significantly increased exclusively in epicardial myocytes, thus abrogating the normal differences between the groups. Dexamethasone increased Ca2+ transients, contractility and SERCA activity in both regions, the latter possibly due to a decrease in total phospholamban (PLB) and an increase PLBpThr17. These results suggest that corticosteroids are powerful modulators of ICaL, Ca2+ transients and contractility in both endo- and epicardial myocytes, while APD and QCa are increased in epicardial myocytes only. This indicates that increased ICaL and SERCA activity rather than QCa are the primary drivers of contractility by adrenocorticoids.
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Affiliation(s)
- Caroline Wacker
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany
| | - Niklas Dams
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany
| | - Alexander Schauer
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany
| | - Anne Ritzer
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany
| | - Tilmann Volk
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany. .,Muscle Research Center Erlangen (MURCE), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
| | - Michael Wagner
- Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraße 6, 91054, Erlangen, Germany. .,Abteilung für Rhythmologie, Herzzentrum Dresden, Fetscherstraße 76, 01307, Dresden, Germany.
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46
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Zeng G, Lian C, Yang P, Zheng M, Ren H, Wang H. E3-ubiquitin ligase TRIM6 aggravates myocardial ischemia/reperfusion injury via promoting STAT1-dependent cardiomyocyte apoptosis. Aging (Albany NY) 2020; 11:3536-3550. [PMID: 31171760 PMCID: PMC6594808 DOI: 10.18632/aging.101995] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/22/2019] [Indexed: 12/26/2022]
Abstract
Cardiomyocyte apoptosis is a major cause of myocardial ischemia/reperfusion (MI/R) injury, in which the activation of the signal transducer and activator of transcription 1 (STAT1) plays an important role. The E3-ubiquitin ligase TRIM6 has been implicated in regulating STAT1 activity, however, whether it is associated with MI/R injury and the underlying mechanism are not determined. In this study, by investigating a mouse MI/R injury model, we show that TRIM6 expression is induced in mouse heart following MI/R injury. Additionally, TRIM6 depletion reduces and its overexpression increases myocardial infarct size, serum creatine phosphokinase (CPK) level and cardiomyocyte apoptosis in mice subjected to MI/R injury, indicating that TRIM6 functions to aggravate MI/R injury. Mechanistically, TRIM6 promotes IKKε-dependent STAT1 activation, and the inhibition of IKKε or STAT1 with the specific inhibitor, CAY10576 or fludarabine, abolishes TRIM6 effects on cardiomyocyte apoptosis and MI/R injury. Similarly, TRIM6 mutant lacking the ability to ubiquitinate IKKε and induce IKKε/STAT1 activation also fails to promote cardiomyocyte apoptosis and MI/R injury. Thus, these results suggest that TRIM6 aggravates MI/R injury through promoting IKKε/STAT1 activation-dependent cardiomyocyte apoptosis, and that TRIM6 might represent a novel therapeutic target for alleviating MI/R injury.
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Affiliation(s)
- Guangwei Zeng
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
| | - Chen Lian
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
| | - Pei Yang
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China.,Jiajiang Oil Storage Warehouse, Xining Joint Service Centre, Xining, China
| | - Mingming Zheng
- Department of Health Economic Managment, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
| | - He Ren
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
| | - Haiyan Wang
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
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Eid RA, Khalil MA, Alkhateeb MA, Eleawa SM, Zaki MSA, El-Kott AF, Al-Shraim M, El-Sayed F, Eldeen MA, Bin-Meferij MM, Awaji KME, Shatoor AS. Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating β-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting β-Catenin. Cardiovasc Drugs Ther 2020; 35:1095-1110. [PMID: 32474680 DOI: 10.1007/s10557-020-07006-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE This study tested if the protective anti-remodeling effect of GLP-1 agonist Exendin-4 after an acute myocardial infarction (MI) in rats involves inhibition of the Wnt1/β-catenin signaling pathway. METHODS Rats were divided into sham, sham + Exendin-4 (10 μg/day, i.p), MI, and MI + Exendin-4. MI was introduced to rats by permanent left anterior descending coronary artery (LAD) ligation. RESULTS On day 7 post-infraction, MI rats showed LV dysfunction with higher serum levels of cardiac markers. Their remote myocardia showed increased mRNA and protein levels of collagen I/III with higher levels of reactive oxygen species (ROS) and inflammatory cytokines, as well as protein levels of Wnt1, phospho-Akt, transforming growth factor (TGF-β1), Smad, phospho-Smad3, α-SMA, caspase-3, and Bax. They also showed higher protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β), as well as total, phosphorylated, and nuclear β-catenin with a concomitant decrease in the levels of cyclic adenosine monophosphate (cAMP), mRNA of manganese superoxide dismutase (MnSOD), and protein levels of Bcl-2, β-arrestin-2, and protein phosphatase-2 (PP2A). Administration of Exendin-4 to MI rats reduced the infarct size and reversed the aforementioned signaling molecules without altering protein levels of TGF-1β and Wnt1 or Akt activation. Interestingly, Exendin-4 increased mRNA levels of MnSOD, protein levels of β-arrestin-2 and PP2A, and β-catenin phosphorylation but reduced the phosphorylation of GSK3β and Smad3, and total β-catenin levels in the LV of control rats. CONCLUSION Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating β-catenin activation and activating β-arrestin-2, PP2A, and GSK3β. Graphical Abstract A graphical abstract that illustrates the mechanisms by which Exendin-4 inhibits cardiac remodeling in remote myocardium of left ventricle MI-induced rats. Mechanisms are assumed to occur in the cardiomyocytes and/or other resident cells such as fibroblast. Β-catenin activation and nuclear translocation are associated with increased synthesis of inflammatory cytokines and transforming growth factor β-1 (TGF-β1). GSK3β is inhibited by phosphorylation at Ser9. Under normal conditions, β-catenin is degraded in the cytoplasm by the active GSK3β-dependent degradation complex (un-phosphorylated) which usually phosphorylates β-catenin at Ser33/37/Thr41. After MI, TGF-β1, and Wnt 1 levels are significantly increased, the overproduction of Wnt1 induces β-catenin stabilization and nuclear translocation through increasing the phosphorylation of disheveled (DVL) protein which in turn phosphorylates and inhibits GSK3β. TGF-β1 stimulates the phosphorylation of Smad-3 and subsequent nuclear translocation to activate the transcription of collage 1/III and α-smooth muscle actin (α-SMA). Besides, TGF-β1 stabilizes cytoplasmic β-catenin levels indirectly by phosphorylation of Akt at Thr308-induced inhibition of GSK3β by increasing phosphorylation of Ser9. Exendin-4, and possibly through G protein-coupled receptors (GPCRs), increases levels of cAMP and upregulates β-arrestin-2 levels. Both can result in a positive inotropic effect. Besides, β-arrestin-2 can stimulate PP2A to dephosphorylation Smad3 (inhibition) and GSK3β (activation), thus reduces fibrosis and prevents the activation of β-catenin and collagen deposition.
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Affiliation(s)
- Refaat A Eid
- Department of Pathology, College of Medicine, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia.
| | - Mohammad Adnan Khalil
- Department of Basic Medical Sciences, Faculty of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mahmoud A Alkhateeb
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Samy M Eleawa
- Department of Applied Medical Sciences, College of Health Sciences, PAAET, Shuwaikh, Kuwait
| | - Mohamed Samir Ahmed Zaki
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia.,Department of Histology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Attalla Farag El-Kott
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia.,Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Mubarak Al-Shraim
- Department of Pathology, College of Medicine, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia
| | - Fahmy El-Sayed
- Department of Pathology, College of Medicine, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia
| | - Muhammad Alaa Eldeen
- Department of Biology, Physiology Section, Faculty of Science, Zagazig University, Zagazig, Egypt
| | | | - Khalid M E Awaji
- Clinical laboratories Department, Asser Central Hospital, Abha, Saudi Arabia
| | - Abdullah S Shatoor
- Department of Clinical Cardiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Cora N, Ghandour J, Pollard CM, Desimine VL, Ferraino KE, Pereyra JM, Valiente R, Lymperopoulos A. Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction. World J Cardiol 2020; 12:192-202. [PMID: 32547713 PMCID: PMC7283997 DOI: 10.4330/wjc.v12.i5.192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/27/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tobacco-related products, containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens, have been clearly associated with coronary artery disease, heart failure, stroke, and other heart diseases. Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system (RAAS) activity. Nicotine, and its major metabolite in humans cotinine, have been reported to induce RAAS activation, resulting in aldosterone elevation in smokers. Aldosterone has various direct and indirect adverse cardiac effects. It is produced by the adrenal cortex in response to angiotensin II (AngII) activating AngII type 1 receptors. RAAS activity increases in chronic smokers, causing raised aldosterone levels (nicotine exposure causes the same in rats). AngII receptors exert their cellular effects via either G proteins or the two βarrestins (βarrestin1 and-2). AIM Since adrenal ßarrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans, we hypothesized that nicotine activates adrenal ßarrestin1, which contributes to RAAS activation and heart disease development. METHODS We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulate βarrestin1 mRNA and protein levels, thereby enhancing AngII-dependent aldosterone synthesis and secretion. RESULTS In contrast, siRNA-mediated βarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295R cells. Importantly, nicotine promotes hyperaldosteronism via adrenal βarrestin1, thereby precipitating cardiac dysfunction, also in vivo, since nicotine-exposed experimental rats with adrenal-specific βarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenal βarrestin1 expression. CONCLUSION Adrenal βarrestin1 upregulation is one of the mechanisms by which tobacco compounds, like nicotine, promote cardio-toxic hyperaldosteronism in vitro and in vivo. Thus, adrenal βarrestin1 represents a novel therapeutic target for tobacco-related heart disease prevention or mitigation.
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Affiliation(s)
- Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Jennifer Ghandour
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Celina Marie Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Victoria Lynn Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Krysten Elaine Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Janelle Marie Pereyra
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Rachel Valiente
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States.
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49
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Liu S, Luttrell LM, Premont RT, Rockey DC. β-Arrestin2 is a critical component of the GPCR-eNOS signalosome. Proc Natl Acad Sci U S A 2020; 117:11483-11492. [PMID: 32404425 PMCID: PMC7261012 DOI: 10.1073/pnas.1922608117] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/31/2020] [Indexed: 12/14/2022] Open
Abstract
Endothelial cell nitric oxide (NO) synthase (eNOS), the enzyme responsible for synthesis of NO in endothelial cells, is regulated by complex posttranslational mechanisms. Sinusoidal portal hypertension, a disorder characterized by liver sinusoidal endothelial cell (SEC) injury with resultant reduced eNOS activity and NO production within the liver, has been associated with defects in eNOS protein-protein interactions and posttranslational modifications. We and others have previously identified novel eNOS interactors, including G protein-coupled receptor (GPCR) kinase interactor 1 (GIT1), which we found to play an unexpected stimulatory role in GPCR-mediated eNOS signaling. Here we report that β-arrestin 2 (β-Arr2), a canonical GPCR signaling partner, localizes in SECs with eNOS in a GIT1/eNOS/NO signaling module. Most importantly, we show that β-Arr2 stimulates eNOS activity, and that β-Arr2 expression is reduced and formation of the GIT1/eNOS/NO signaling module is interrupted during liver injury. In β-Arr2-deficient mice, bile duct ligation injury (BDL) led to significantly reduced eNOS activity and to a dramatic increase in portal hypertension compared to BDL in wild-type mice. Overexpression of β-Arr2 in injured or β-Arr2-deficient SECs rescued eNOS function by increasing eNOS complex formation and NO production. We also found that β-Arr2-mediated GIT1/eNOS complex formation is dependent on Erk1/2 and Src, two kinases known to interact with and be activated by β-Arr2 in response to GCPR activation. Our data emphasize that β-Arr2 is an integral component of the GIT1/eNOS/NO signaling pathway and have implications for the pathogenesis of sinusoidal portal hypertension.
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Affiliation(s)
- Songling Liu
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425
| | - Louis M Luttrell
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425
| | - Richard T Premont
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106
| | - Don C Rockey
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425;
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50
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Maning J, McCrink KA, Pollard CM, Desimine VL, Ghandour J, Perez A, Cora N, Ferraino KE, Parker BM, Brill AR, Aukszi B, Lymperopoulos A. Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. Int J Mol Sci 2020; 21:2868. [PMID: 32326036 PMCID: PMC7215681 DOI: 10.3390/ijms21082868] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022] Open
Abstract
Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon β2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. β2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via β2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.
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Affiliation(s)
- Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Katie A. McCrink
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Celina M. Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Victoria L. Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Jennifer Ghandour
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Arianna Perez
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Krysten E. Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Barbara M. Parker
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Ava R. Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Beatrix Aukszi
- Department of Chemistry and Physics, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
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