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Parichatikanond W, Duangrat R, Kurose H, Mangmool S. Regulation of β-Adrenergic Receptors in the Heart: A Review on Emerging Therapeutic Strategies for Heart Failure. Cells 2024; 13:1674. [PMID: 39451192 PMCID: PMC11506672 DOI: 10.3390/cells13201674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/24/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
The prolonged overstimulation of β-adrenergic receptors (β-ARs), a member of the G protein-coupled receptor (GPCR) family, causes abnormalities in the density and functionality of the receptor and contributes to cardiac dysfunctions, leading to the development and progression of heart diseases, especially heart failure (HF). Despite recent advancements in HF therapy, mortality and morbidity rates continue to be high. Treatment with β-AR antagonists (β-blockers) has improved clinical outcomes and reduced overall hospitalization and mortality rates. However, several barriers in the management of HF remain, providing opportunities to develop new strategies that focus on the functions and signal transduction of β-ARs involved in the pathogenesis of HF. As β-AR can signal through multiple pathways influenced by different receptor subtypes, expression levels, and signaling components such as G proteins, G protein-coupled receptor kinases (GRKs), β-arrestins, and downstream effectors, it presents a complex mechanism that could be targeted in HF management. In this narrative review, we focus on the regulation of β-ARs at the receptor, G protein, and effector loci, as well as their signal transductions in the physiology and pathophysiology of the heart. The discovery of potential ligands for β-AR that activate cardioprotective pathways while limiting off-target signaling is promising for the treatment of HF. However, applying findings from preclinical animal models to human patients faces several challenges, including species differences, the genetic variability of β-ARs, and the complexity and heterogeneity of humans. In this review, we also summarize recent updates and future research on the regulation of β-ARs in the molecular basis of HF and highlight potential therapeutic strategies for HF.
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Affiliation(s)
| | - Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Hitoshi Kurose
- Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan;
- Pharmacology for Life Sciences, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Supachoke Mangmool
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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Strom J, Bull M, Gohlke J, Saripalli C, Methawasin M, Gotthardt M, Granzier H. Titin's cardiac-specific N2B element is critical to mechanotransduction during volume overload of the heart. J Mol Cell Cardiol 2024; 191:40-49. [PMID: 38604403 PMCID: PMC11229416 DOI: 10.1016/j.yjmcc.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 03/09/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which has been proposed to function as a mechanosensor. To assess its significance, we conducted experiments using N2B knockout (KO) mice and wildtype (WT) mice, subjecting them to three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2) volume overload caused by aortocaval fistula (ACF), and 3) exercise-induced hypertrophy through swimming. Under conditions of pressure overload (TAC), both genotypes exhibited similar hypertrophic responses. In contrast, WT mice displayed robust left ventricular hypertrophy after one week of volume overload (ACF), while the KO mice failed to undergo hypertrophy and experienced a high mortality rate. Similarly, swim exercise-induced hypertrophy was significantly reduced in the KO mice. RNA-Seq analysis revealed an abnormal β-adrenergic response to volume overload in the KO mice, as well as a diminished response to isoproterenol-induced hypertrophy. Because it is known that the N2B element interacts with the four-and-a-half LIM domains 1 and 2 (FHL1 and FHL2) proteins, both of which have been associated with mechanotransduction, we evaluated these proteins. Interestingly, while volume-overload resulted in FHL1 protein expression levels that were comparable between KO and WT mice, FHL2 protein levels were reduced by over 90% in the KO mice compared to WT. This suggests that in response to volume overload, FHL2 might act as a signaling mediator between the N2B element and downstream signaling pathways. Overall, our study highlights the importance of the N2B element in mechanosensing during volume overload, both in physiological and pathological settings.
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Affiliation(s)
- Joshua Strom
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America
| | - Mathew Bull
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America
| | - Jochen Gohlke
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America
| | - Chandra Saripalli
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America
| | - Mei Methawasin
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America
| | - Michael Gotthardt
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Henk Granzier
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America.
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Russell JJ, Mummidi S, DeMarco VG, Grisanti LA, Bailey CA, Bender SB, Chandrasekar B. Integrated miRNA-mRNA networks underlie attenuation of chronic β-adrenergic stimulation-induced cardiac remodeling by minocycline. Physiol Genomics 2024; 56:360-366. [PMID: 38314697 PMCID: PMC11283891 DOI: 10.1152/physiolgenomics.00140.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/18/2024] [Accepted: 02/01/2024] [Indexed: 02/07/2024] Open
Abstract
Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although β-adrenergic receptor (β-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic β-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome.
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Affiliation(s)
- Jacob J Russell
- Biomedical Sciences, University of Missouri, Columbia, Missouri, United States
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Srinivas Mummidi
- Health and Behavior Sciences, Texas A&M University-San Antonio, San Antonio, Texas, United States
| | - Vincent G DeMarco
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
- Medicine, University of Missouri School of Medicine, Columbia, Missouri, United States
| | - Laurel A Grisanti
- Biomedical Sciences, University of Missouri, Columbia, Missouri, United States
| | - Chastidy A Bailey
- Biomedical Sciences, University of Missouri, Columbia, Missouri, United States
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Shawn B Bender
- Biomedical Sciences, University of Missouri, Columbia, Missouri, United States
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
- Dalton Cardiovascular Center, University of Missouri, Columbia, Missouri, United States
| | - Bysani Chandrasekar
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
- Medicine, University of Missouri School of Medicine, Columbia, Missouri, United States
- Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, United States
- Dalton Cardiovascular Center, University of Missouri, Columbia, Missouri, United States
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Alonazi AS, Bin Dayel AF, Albuaijan DA, Bin Osfur AS, Hakami FM, Alzayed SS, Almotairi AR, Khan MR, Alharbi HM, Ali RA, Alamin MA, Alghibiwi HK, Alrasheed NM, Alhosaini KA. Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression. Int J Mol Sci 2023; 24:17270. [PMID: 38139099 PMCID: PMC10743803 DOI: 10.3390/ijms242417270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
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Affiliation(s)
- Asma S. Alonazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Anfal F. Bin Dayel
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Danah A. Albuaijan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Alhanouf S. Bin Osfur
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Fatemah M. Hakami
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Shaden S. Alzayed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Ahmad R. Almotairi
- Department of Pathology, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad R. Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Hana M. Alharbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Rehab A. Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Maha A. Alamin
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Hanan K. Alghibiwi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Nouf M. Alrasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
| | - Khaled A. Alhosaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.F.B.D.)
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de Moura AL, Brum PC, de Carvalho AETS, Spadari RC. Effect of stress on the chronotropic and inotropic responses to β-adrenergic agonists in isolated atria of KOβ2 mice. Life Sci 2023; 322:121644. [PMID: 37004731 DOI: 10.1016/j.lfs.2023.121644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/06/2023] [Accepted: 03/26/2023] [Indexed: 04/03/2023]
Abstract
Altered sensitivity to the chronotropic and inotropic effects of catecholamines and reduction in β1/β2-adrenoceptor (β1/β2-AR) ratio were reported in failing and in senescent human heart, as well as in isolated atria and ventricle of rats submitted to stress. This was due to downregulation of β1-AR with or without up-regulation of β2-AR. AIMS To investigate the stress-induced behavior of β1-AR in the heart of mice expressing a non-functional β2-AR subtype. The guiding hypothesis is that the absence of β2-AR signaling will not affect the behavior of β1-AR during stress and that those are independent processes. MATERIALS AND METHODS The chronotropic and inotropic responses to β-AR agonists in isolated atria of stressed mice expressing a non-functional β2-AR were analyzed. The mRNA and protein expressions of β1- and β2-AR were also determined. KEY FINDINGS No deaths were observed in mice under stress protocol. Atria of stressed mice displayed reduced sensitivity to isoprenaline compared to the controls, an effect that was abolished by the β2- and β1-AR antagonists 50 nM ICI118,551 and 300 nM CGP20712A, respectively. Sensitivity and maximum response to the β-agonists dobutamine and salbutamol were not altered by stress or ICI118,551. The responses to dobutamine and salbutamol were prevented by CGP20712A. The expression of β1-AR was reduced at protein levels. SIGNIFICANCE Collectively, our data provide evidence that the cardiac β2-AR is not essential for survival in a stressful situation and that the stress-induced reduction of β1-AR expression was independent of the β2-AR presence.
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice. Biomedicines 2023; 11:biomedicines11030662. [PMID: 36979641 PMCID: PMC10045486 DOI: 10.3390/biomedicines11030662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/24/2023] Open
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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Harnessing RKIP to Combat Heart Disease and Cancer. Cancers (Basel) 2022; 14:cancers14040867. [PMID: 35205615 PMCID: PMC8870036 DOI: 10.3390/cancers14040867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.
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Sergienko NM, Donner DG, Delbridge LMD, McMullen JR, Weeks KL. Protein phosphatase 2A in the healthy and failing heart: New insights and therapeutic opportunities. Cell Signal 2021; 91:110213. [PMID: 34902541 DOI: 10.1016/j.cellsig.2021.110213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023]
Abstract
Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, β-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56α and PP2A/B56ε) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.
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Affiliation(s)
- Nicola M Sergienko
- Baker Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Central Clinical School, Monash University, Clayton VIC 3800, Australia
| | - Daniel G Donner
- Baker Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville VIC 3010, Australia
| | - Lea M D Delbridge
- Department of Anatomy and Physiology, The University of Melbourne, Parkville VIC 3010, Australia
| | - Julie R McMullen
- Baker Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville VIC 3010, Australia; Department of Physiology and Department of Medicine Alfred Hospital, Monash University, Clayton VIC 3800, Australia; Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora VIC 3086, Australia; Department of Diabetes, Central Clinical School, Monash University, Clayton VIC 3800, Australia.
| | - Kate L Weeks
- Baker Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Department of Anatomy and Physiology, The University of Melbourne, Parkville VIC 3010, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville VIC 3010, Australia; Department of Diabetes, Central Clinical School, Monash University, Clayton VIC 3800, Australia.
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Feng H, Xie B, Zhang Z, Yan J, Cheng M, Zhou Y. MiR-135a Protects against Myocardial Injury by Targeting TLR4. Chem Pharm Bull (Tokyo) 2021; 69:529-536. [PMID: 34078799 DOI: 10.1248/cpb.c20-01003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Emerging evidence highlights the importance of microRNAs (miRNAs) as functional regulators in cardiovascular disease. This study aimed to investigate the functional significance of miR-135a in the regulation of cardiac injury after isoprenaline (ISO) stimulation and the underlying mechanisms of its effects. Murine models with cardiac-specific overexpression of miR-135a were constructed with an adeno-associated virus expression system. The cardiac injury model was induced by ISO injection (60 mg/kg per day for 14 d). In vitro, we used H9c2 cells to establish a cell injury model by ISO stimulation (10 µM). The results indicated that miR-135a was increased during days 0-6 of ISO injection and was then downregulated during days 8-14 of ISO injection. The expression of miR-135a was consistent with the in vivo findings. Moreover, mice with cardiac overexpression of miR-135a exhibited reduced cardiac fibrosis, lactate dehydrogenase levels, Troponin I, inflammatory response and apoptosis. Overexpression of miR-135a also ameliorated cardiac dysfunction induced by ISO. MiR-135 overexpression in H9c2 cells increased cell viability and decreased cell apoptosis and inflammation in response to ISO. Conversely, miR-135 silencing in H9c2 cells decreased cell viability and increased cell apoptosis and inflammation in response to ISO. Mechanistically, we found that miR-135a negatively regulated toll-like receptor 4 (TLR4), which was confirmed by luciferase assay. Furthermore, the TLR4 inhibitor eritoran abolished the adverse effect of miR-135 silencing. Overall, miR-135a promotes ISO-induced cardiac injury by inhibiting the TLR4 pathway. MiR-135a may be a therapeutic agent for cardiac injury.
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Affiliation(s)
- Hui Feng
- Department of Cardiology, The First Affiliated Hospital of Soochow University.,Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University
| | - Bing Xie
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University
| | - Zhuoqi Zhang
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University
| | - Jun Yan
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University
| | - Mingyue Cheng
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University
| | - Yafeng Zhou
- Department of Cardiology, The First Affiliated Hospital of Soochow University
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El Khoudary SR, Fabio A, Yester JW, Steinhauser ML, Christopher AB, Gyngard F, Adams PS, Morell VO, Viegas M, Da Silva JP, Da Silva LF, Castro-Medina M, McCormick A, Reyes-Múgica M, Barlas M, Liu H, Thomas D, Ammanamanchi N, Sada R, Cuda M, Hartigan E, Groscost DK, Kühn B. Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot. Int J Cardiol 2021; 339:36-42. [PMID: 34265312 DOI: 10.1016/j.ijcard.2021.07.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the β-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. METHODS Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. CONCLUSION This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension. CLINICAL TRIAL REGISTRATION The trial protocol was registered at clinicaltrials.gov (NCT04713657).
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Affiliation(s)
- Samar R El Khoudary
- Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh
| | - Anthony Fabio
- Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh
| | - Jessie W Yester
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Matthew L Steinhauser
- Aging Institute, University of Pittsburgh, Bridgeside Point 1, 5th Floor, 100 Technology Drive, Pittsburgh, PA 15219, USA; UPMC Heart and Vascular Institute, UPMC Presbyterian, 200 Lothrop St., Pittsburgh, PA 15213, USA
| | - Adam B Christopher
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Frank Gyngard
- Center for NanoImaging, Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne St, Rm 535, Cambridge, MA 02139, USA
| | - Phillip S Adams
- Department of Anesthesiology and Perioperative Medicine, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Victor O Morell
- Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Melita Viegas
- Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Jose P Da Silva
- Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Luciana F Da Silva
- Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Mario Castro-Medina
- Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Andrew McCormick
- Vascular Anomaly Center, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Miguel Reyes-Múgica
- Division of Pediatric Pathology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Michelle Barlas
- Investigational Drug Service, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Honghai Liu
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Dawn Thomas
- Clinical Research Support Services (CRSS), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Niyatie Ammanamanchi
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Rachel Sada
- Clinical Research Support Services (CRSS), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Megan Cuda
- Clinical Research Support Services (CRSS), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Elizabeth Hartigan
- Clinical Research Support Services (CRSS), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - David K Groscost
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA
| | - Bernhard Kühn
- Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
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11
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ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth. BIOLOGY 2021; 10:biology10040346. [PMID: 33923899 PMCID: PMC8072600 DOI: 10.3390/biology10040346] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/24/2022]
Abstract
Integration of cellular responses to extracellular cues is essential for cell survival and adaptation to stress. Extracellular signal-regulated kinase (ERK) 1 and 2 serve an evolutionarily conserved role for intracellular signal transduction that proved critical for cardiomyocyte homeostasis and cardiac stress responses. Considering the importance of ERK1/2 in the heart, understanding how these kinases operate in both normal and disease states is critical. Here, we review the complexity of upstream and downstream signals that govern ERK1/2-dependent regulation of cardiac structure and function. Particular emphasis is given to cardiomyocyte hypertrophy as an outcome of ERK1/2 activation regulation in the heart.
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12
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CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor. Sci Rep 2021; 11:3426. [PMID: 33564089 PMCID: PMC7873251 DOI: 10.1038/s41598-021-83022-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/28/2021] [Indexed: 02/08/2023] Open
Abstract
Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
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13
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Cirillo F, Piccoli M, Ghiroldi A, Monasky MM, Rota P, La Rocca P, Tarantino A, D'Imperio S, Signorelli P, Pappone C, Anastasia L. The antithetic role of ceramide and sphingosine-1-phosphate in cardiac dysfunction. J Cell Physiol 2021; 236:4857-4873. [PMID: 33432663 DOI: 10.1002/jcp.30235] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/27/2022]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine-1-phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so-called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs.
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Affiliation(s)
- Federica Cirillo
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy
| | - Marco Piccoli
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy
| | - Andrea Ghiroldi
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy
| | | | - Paola Rota
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Paolo La Rocca
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Adriana Tarantino
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy.,Department of Arrhythmology, IRCCS Policlinico San Donato, Milan, Italy
| | - Sara D'Imperio
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy.,Department of Arrhythmology, IRCCS Policlinico San Donato, Milan, Italy
| | - Paola Signorelli
- Department of Health Sciences, Biochemistry and Molecular Biology Laboratory, University of Milan, Milan, Italy
| | - Carlo Pappone
- Department of Arrhythmology, IRCCS Policlinico San Donato, Milan, Italy.,Faculty of Medicine and Surgery, University of Vita-Salute San Raffaele, Milan, Italy
| | - Luigi Anastasia
- Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy.,Faculty of Medicine and Surgery, University of Vita-Salute San Raffaele, Milan, Italy
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14
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Khalilimeybodi A, Paap AM, Christiansen SLM, Saucerman JJ. Context-specific network modeling identifies new crosstalk in β-adrenergic cardiac hypertrophy. PLoS Comput Biol 2020; 16:e1008490. [PMID: 33338038 PMCID: PMC7781532 DOI: 10.1371/journal.pcbi.1008490] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 01/04/2021] [Accepted: 11/05/2020] [Indexed: 11/25/2022] Open
Abstract
Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model’s predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in β-adrenergic cardiac hypertrophy. Pathological cardiac hypertrophy is a disease in which the heart grows abnormally in response to different motivators such as high blood pressure or variations in hormones and growth factors. The shape of the heart after its growth depends on the context in which it grows. Since cell signaling in the cardiac cells plays a key role in the determination of heart shape, a thorough understanding of cardiac cells signaling in each context enlightens the mechanisms which control response of cardiac cells. However, cell signaling in cardiac hypertrophy comprises a complex web of pathways with numerous interactions, and predicting how these interactions control the hypertrophic signal in each context is not achievable by only experiments or general computational models. To address this need, we developed an approach to bring together the experimental data of each context with a signaling network curated from literature to identify the main players of cardiac cells response in each context and attain the context-specific models of cardiac hypertrophy. By utilizing our approach, we identified the main regulators of cardiac hypertrophy in four important contexts. We developed a network model of β-adrenergic cardiac hypertrophy, and predicted and validated new interactions that regulate cardiac cells response in this context.
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Affiliation(s)
- Ali Khalilimeybodi
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Alexander M. Paap
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Steven L. M. Christiansen
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Jeffrey J. Saucerman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail:
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15
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Takano APC, Senger N, Barreto-Chaves MLM. The endocrinological component and signaling pathways associated to cardiac hypertrophy. Mol Cell Endocrinol 2020; 518:110972. [PMID: 32777452 DOI: 10.1016/j.mce.2020.110972] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 07/14/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
Although myocardial growth corresponds to an adaptive response to maintain cardiac contractile function, the cardiac hypertrophy is a condition that occurs in many cardiovascular diseases and typically precedes the onset of heart failure. Different endocrine factors such as thyroid hormones, insulin, insulin-like growth factor 1 (IGF-1), angiotensin II (Ang II), endothelin (ET-1), catecholamines, estrogen, among others represent important stimuli to cardiomyocyte hypertrophy. Thus, numerous endocrine disorders manifested as changes in the local environment or multiple organ systems are especially important in the context of progression from cardiac hypertrophy to heart failure. Based on that information, this review summarizes experimental findings regarding the influence of such hormones upon signalling pathways associated with cardiac hypertrophy. Understanding mechanisms through which hormones differentially regulate cardiac hypertrophy could open ways to obtain therapeutic approaches that contribute to prevent or delay the onset of heart failure related to endocrine diseases.
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Affiliation(s)
| | - Nathalia Senger
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
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16
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Tomasovic A, Brand T, Schanbacher C, Kramer S, Hümmert MW, Godoy P, Schmidt-Heck W, Nordbeck P, Ludwig J, Homann S, Wiegering A, Shaykhutdinov T, Kratz C, Knüchel R, Müller-Hermelink HK, Rosenwald A, Frey N, Eichler J, Dobrev D, El-Armouche A, Hengstler JG, Müller OJ, Hinrichs K, Cuello F, Zernecke A, Lorenz K. Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects. Nat Commun 2020; 11:1733. [PMID: 32265441 PMCID: PMC7138859 DOI: 10.1038/s41467-020-15505-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 03/13/2020] [Indexed: 12/16/2022] Open
Abstract
Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes. Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.
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Affiliation(s)
- Angela Tomasovic
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany.,Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
| | - Theresa Brand
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany.,Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
| | - Constanze Schanbacher
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany.,Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany
| | - Sofia Kramer
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
| | - Martin W Hümmert
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany.,Department of Neurology, Hannover Medical School, 30625, Hannover, Germany
| | - Patricio Godoy
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139, Dortmund, Germany
| | - Wolfgang Schmidt-Heck
- Leibniz Institute for Natural Product Research and Infection Biology -Hans Knoell Institute-, 07745, Jena, Germany
| | - Peter Nordbeck
- Comprehensive Heart Failure Center, 97078, Würzburg, Germany
| | - Jonas Ludwig
- Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058, Erlangen, Germany
| | - Susanne Homann
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany
| | - Armin Wiegering
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital of Würzburg, 97080, Würzburg, Germany
| | - Timur Shaykhutdinov
- Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
| | - Christoph Kratz
- Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
| | - Ruth Knüchel
- Institute of Pathology, University Hospital Aachen, RWTH Aachen, 52074, Aachen, Germany
| | | | - Andreas Rosenwald
- Institute of Pathology, University of Würzburg, 97080, Würzburg, Germany
| | - Norbert Frey
- Department of Internal Medicine III, University of Kiel, 24105, Kiel, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Jutta Eichler
- Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058, Erlangen, Germany
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, 45147, Essen, Germany
| | - Ali El-Armouche
- Department of Pharmacology and Toxicology, TU Dresden, 01307, Dresden, Germany
| | - Jan G Hengstler
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139, Dortmund, Germany
| | - Oliver J Müller
- Department of Internal Medicine III, University of Kiel, 24105, Kiel, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Karsten Hinrichs
- Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 12489, Berlin, Germany
| | - Friederike Cuello
- Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine, University Hospital Würzburg, University of Würzburg, 97080, Würzburg, Germany
| | - Kristina Lorenz
- Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany. .,Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., 44139, Dortmund, Germany. .,Comprehensive Heart Failure Center, 97078, Würzburg, Germany.
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17
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Lam B, Roudier E. Considering the Role of Murine Double Minute 2 in the Cardiovascular System? Front Cell Dev Biol 2020; 7:320. [PMID: 31921839 PMCID: PMC6916148 DOI: 10.3389/fcell.2019.00320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/21/2019] [Indexed: 01/26/2023] Open
Abstract
The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.
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Affiliation(s)
- Brian Lam
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
| | - Emilie Roudier
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
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18
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Sugiyama A, Okada M, Yamawaki H. Canstatin suppresses isoproterenol-induced cardiac hypertrophy through inhibition of calcineurin/nuclear factor of activated T-cells pathway in rats. Eur J Pharmacol 2019; 871:172849. [PMID: 31843516 DOI: 10.1016/j.ejphar.2019.172849] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 11/27/2019] [Accepted: 12/09/2019] [Indexed: 12/14/2022]
Abstract
Pathological cardiac hypertrophy associated with cardiac dysfunction is an independent risk factor for arrhythmia, myocardial infarction and sudden death. Canstatin, a C-terminal fragment of type IV collagen α2 chain, is abundantly expressed in normal heart tissue. We previously demonstrated that canstatin inhibits isoproterenol (ISO)-induced dephosphorylation of nuclear factor of activated T-cells (NFAT)c4, which plays an important role in cardiac hypertrophy, in differentiated H9c2 cardiomyoblasts. Thus, we investigated whether in vivo canstatin administration prevents ISO-induced cardiac hypertrophy through the inhibition of NFATc4 pathway. Rats were subcutaneously injected with ISO (5 mg/kg) or saline (Cont) for 7 days. Simultaneously, recombinant mouse canstatin (20 μg/kg) or vehicle was intraperitoneally administered. After left ventricular wall thickness and cardiac function were measured by echocardiography, the hearts were isolated and left ventricular weight (LVW) was weighed. Azan staining was performed to measure cross-sectional diameter of cardiomyocytes. Activity of calcineurin, which dephosphorylates NFATc4, was measured by calcineurin phosphatase activity assay. Immunohistochemical staining was performed to evaluate nuclear translocation of NFATc4. Intracellular Ca2+ concentration in neonatal rat cardiomyocytes (NRCMs) was measured by using a calcium indicator. Canstatin significantly inhibited ISO-induced increase of LVW, left ventricular posterior wall thickness at end-diastole and diameter of cardiomyocytes. Canstatin significantly inhibited ISO-induced activation of calcineurin, nuclear translocation of NFATc4, increased mRNA expression of β-myosin heavy chain and α-skeletal actin, and intracellular Ca2+ rise in NRCMs. In summary, we for the first time demonstrated that canstatin administration suppresses ISO-induced cardiac hypertrophy possibly through the blockade of calcineurin/NFATc4 pathway in rats.
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Affiliation(s)
- Akira Sugiyama
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
| | - Muneyoshi Okada
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan.
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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19
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Abstract
The term uraemic cardiomyopathy refers to the cardiac abnormalities that are seen in patients with chronic kidney disease (CKD). Historically, this term was used to describe a severe cardiomyopathy that was associated with end-stage renal disease and characterized by severe functional abnormalities that could be reversed following renal transplantation. In a modern context, uraemic cardiomyopathy describes the clinical phenotype of cardiac disease that accompanies CKD and is perhaps best characterized as diastolic dysfunction seen in conjunction with left ventricular hypertrophy and fibrosis. A multitude of factors may contribute to the pathogenesis of uraemic cardiomyopathy, and current treatments only modestly improve outcomes. In this Review, we focus on evolving concepts regarding the roles of fibroblast growth factor 23 (FGF23), inflammation and systemic oxidant stress and their interactions with more established mechanisms such as pressure and volume overload resulting from hypertension and anaemia, respectively, activation of the renin-angiotensin and sympathetic nervous systems, activation of the transforming growth factor-β (TGFβ) pathway, abnormal mineral metabolism and increased levels of endogenous cardiotonic steroids.
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Affiliation(s)
- Xiaoliang Wang
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
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20
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Chen Y, Beng H, Su H, Han F, Fan Z, Lv N, Jovanović A, Tan W. Isosteviol prevents the development of isoprenaline‑induced myocardial hypertrophy. Int J Mol Med 2019; 44:1932-1942. [PMID: 31545484 PMCID: PMC6777692 DOI: 10.3892/ijmm.2019.4342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/30/2019] [Indexed: 11/06/2022] Open
Abstract
Isosteviol sodium (STVNa), which is a derivate of the natural sweet-tasting glycoside stevioside, has recently been developed and it has been determined that this compound exhibits neuro- and cardio-protective properties. In the current study, whether STVNa interferes with the development of cardiac hypertrophy, which is induced by isoprenaline (Iso), was investigated in an experimental rat model. Rats were treated with a vehicle (0.9% NaCl; control), isoprenaline (Iso; 5 mg/kg) or Iso (5 mg/kg) with STVNa (4 mg/kg; Iso + STVNa). Cardiomyocytes were isolated using enzymatic dissociation and were treated with 5 µM Iso for 24 h and co-treated with 5 µM STVNa. Brain natriuretic peptide (BNP) mRNA expression was determined using PCR analysis. Cell surface area, intracellular reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), cytoplasmic Ca2+ and Ca2+ and contractile function were examined using a laser scanning confocal microscope. The current study demonstrated that STVNa inhibited Iso-induced cardiac hypertrophy by inhibiting cardiomyocyte size. STVNa significantly reduced cell surface area and decreased BNP mRNA expression in ventricular cardiomyocyte Iso-induced hypertrophy. STVNa was also revealed to restore ΔΨm and reduce ROS generation and intracellular Ca2+ concentration when compared with the Iso-treated group. Additionally, STVNa preserved Ca2+ transients in hypertrophic cardiomyocytes. In conclusion, the present study demonstrated that STVNa protects against Iso-induced myocardial hypertrophy by reducing oxidative stress, restoring ΔΨm and maintaining Ca2+ homeostasis.
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Affiliation(s)
- Yaoxu Chen
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Huimin Beng
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Hao Su
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Fuping Han
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Zhuo Fan
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Nanying Lv
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
| | - Aleksandar Jovanović
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, CY‑1700 Nicosia, Cyprus
| | - Wen Tan
- Department of Innovative Drugs and Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong 510641, P.R. China
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21
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Ashraf S, Hegazy YK, Harmancey R. Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes. Am J Physiol Cell Physiol 2019; 317:C513-C524. [PMID: 31188636 PMCID: PMC6766613 DOI: 10.1152/ajpcell.00526.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 h) increase in NR4A2 levels that was accompanied by a transient (<24 h) increase in nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 to similar levels modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. Consistent with those findings, NR4A2 overexpression also blocked the phosphorylative activation of growth-related kinases ERK1/2, Akt, and p70 S6 kinase. Prominent among the transcriptional changes induced by NR4A2 was the upregulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pretreatment of NR4A2-overexpressing cardiomyocytes with the DUSP inhibitor BCI [(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one] prevented the inhibition of ERK1/2 following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the β-adrenergic receptor-mediated growth response in cardiomyocytes and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.
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Affiliation(s)
- Sadia Ashraf
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Yassmin K Hegazy
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Romain Harmancey
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi.,Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi
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22
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Breitenbach T, Lorenz K, Dandekar T. How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency. Int J Mol Sci 2019; 20:E2179. [PMID: 31052520 PMCID: PMC6539830 DOI: 10.3390/ijms20092179] [Citation(s) in RCA: 12] [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: 03/06/2019] [Revised: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 12/13/2022] Open
Abstract
Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.
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Affiliation(s)
- Tim Breitenbach
- Biozentrum, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
| | - Kristina Lorenz
- Institute of Pharmacology and Toxicology, Versbacher Straße 9, 97078 Würzburg, Germany.
- Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.
| | - Thomas Dandekar
- Biozentrum, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
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23
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ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy. Int J Mol Sci 2019; 20:ijms20092164. [PMID: 31052420 PMCID: PMC6539093 DOI: 10.3390/ijms20092164] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/26/2019] [Accepted: 04/29/2019] [Indexed: 12/17/2022] Open
Abstract
Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context.
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24
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Tóth AD, Schell R, Lévay M, Vettel C, Theis P, Haslinger C, Alban F, Werhahn S, Frischbier L, Krebs-Haupenthal J, Thomas D, Gröne HJ, Avkiran M, Katus HA, Wieland T, Backs J. Inflammation leads through PGE/EP 3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes. EMBO Mol Med 2019; 10:emmm.201708536. [PMID: 29907596 PMCID: PMC6034133 DOI: 10.15252/emmm.201708536] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the βγ subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21-activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de-repress MEF2. In vivo, endotoxemia in MEF2-reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de-repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.
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Affiliation(s)
- András D Tóth
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.,Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Richard Schell
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.,Department of Cardiology, Heidelberg University, Heidelberg, Germany
| | - Magdolna Lévay
- DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.,Experimental Pharmacology, European Center of Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christiane Vettel
- DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.,Experimental Pharmacology, European Center of Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philipp Theis
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Clemens Haslinger
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Felix Alban
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Stefanie Werhahn
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Lina Frischbier
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Jutta Krebs-Haupenthal
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
| | - Dominique Thomas
- Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany
| | - Hermann-Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Metin Avkiran
- Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas' Hospital, London, UK
| | - Hugo A Katus
- Department of Cardiology, Heidelberg University, Heidelberg, Germany
| | - Thomas Wieland
- DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.,Experimental Pharmacology, European Center of Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Backs
- Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany .,DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany
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25
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Lethal immunoglobulins: Autoantibodies and sudden cardiac death. Autoimmun Rev 2019; 18:415-425. [DOI: 10.1016/j.autrev.2018.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 12/13/2018] [Indexed: 02/08/2023]
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26
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Zhang M, Du Q, Yang F, Guo Y, Hou Y, Zhu P. Acupuncture at PC6 prevents cardiac hypertrophy in isoproterenol-treated mice. Acupunct Med 2019; 37:55-63. [PMID: 30843422 DOI: 10.1136/acupmed-2017-011418] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES To investigate the effect of acupuncture at PC6 on cardiac hypertrophy in isoproterenol (ISO)-treated mice. METHODS 48 male C57BL/6 mice underwent subcutaneous injection of ISO for 14 days and were randomly divided into four groups (n=12 each) that remained untreated (ISO group), received verum manual acupuncture (MA) treatment at PC6 (ISO+MA(PC6) group), sham MA at location on the tail not corresponding to any traditional acupuncture point (ISO+MA(tail) group), or propranolol (ISO+PR group). An additional 12 mice were given an injection of phosphate-buffered saline (PBS) and formed a healthy control (Normal) group. After performing echocardiography and measuring the ratio of heart weight (HW)/tibia length (TL) at 14 days, all mice were euthanased. Morphological examination was performed following haematoxylin and eosin and Masson's staining of heart tissues. Ultrastructural changes were observed by electron microscopy. Cardiac protein expression of atrial natriuretic peptide (ANP) and tumour necrosis factor α (TNFα) were measured by immunohistochemical (IHC) staining and Western blotting. RESULTS Compared with the untreated model group, acupuncture at PC6 lowered the heart rate, reduced the ratio of HW/TL, improved the left ventricular (LV) anterior wall thickness (LVAWd), LV end-diastolic anterior wall thickness (LVAWs), LV end-systolic posterior wall thickness (LVPWd), LV end-diastolic posterior wall thickness (LVPWs), and fractional shortening (FS) as observed by echocardiography (ISO+MA(PC6) vs. ISO groups: P<0.05). Moreover, evidence from morphological studies demonstrated that acupuncture at PC6 inhibited myocardial hypertrophy and collagen deposition, and normalised the ultrastructural changes. In addition, ANP and TNFα expression were attenuated in the verum acupuncture group compared with the untreated model group (ISO+MA(PC6) vs. ISO groups: P<0.05). CONCLUSIONS The results demonstrated that acupuncture at PC6 attenuates sympathetic overactivity. Additionally, it may improve cardiac performance by reversing adverse cardiac remodelling. Acupuncture has potential as a treatment for sympathetic hypertension.
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Affiliation(s)
- Miao Zhang
- 1 Second Affiliated Hospital of Heilongjiang TCM University, Harbin, China
| | - Qigen Du
- 1 Second Affiliated Hospital of Heilongjiang TCM University, Harbin, China
| | - Fubiao Yang
- 2 Department of Medical Affairs, Heilongjiang TCM University, Harbin, China
| | - Ying Guo
- 1 Second Affiliated Hospital of Heilongjiang TCM University, Harbin, China
| | - Yunlong Hou
- 3 Department of Pharmacology, Harbin Medical University, Harbin, China
| | - Pengyu Zhu
- 1 Second Affiliated Hospital of Heilongjiang TCM University, Harbin, China
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27
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Hanson KR, Ware WA. Myocardial hypertrophy associated with long-term phenylpropanolamine use in a dog. J Am Vet Med Assoc 2018; 253:1452-1459. [PMID: 30451619 DOI: 10.2460/javma.253.11.1452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
CASE DESCRIPTION A 9-year-old spayed female Dalmatian was examined because of progressive pelvic limb paraparesis. CLINICAL FINDINGS The dog had a history of chronic urinary incontinence and had been treated with phenylpropanolamine (PPA) for almost 8.5 years. Intervertebral disk disease at T12-13 was diagnosed, and a hemilaminectomy was performed. Three days after surgery, the dog developed a ventricular tachyarrhythmia. Severe left and mild right ventricular hypertrophy were detected by echocardiography. TREATMENT AND OUTCOME The arrhythmia was controlled with sotalol. Phenylpropanolamine administration was discontinued immediately before surgery and was not resumed. Heart rate and rhythm and blood pressure were within reference limits, and the ventricular hypertrophy had almost completely resolved 5 months later. Sotalol administration was discontinued. Shortly after the 5-month recheck evaluation, PPA administration was resumed, albeit at a lower dosage than that before surgery, for control of urinary incontinence. At the 10-month recheck evaluation, the dog was hypertensive and ventricular hypertrophy had recurred. Discontinuation of PPA administration was recommended but not heeded. The dog developed marked azotemia 1.5 years after surgery, which was managed by the referring veterinarian, and was subsequently lost to follow-up. CLINICAL RELEVANCE The fact that the ventricular hypertrophy almost completely resolved when PPA administration was discontinued and then recurred after it was resumed strongly suggested the drug was an important contributing factor to the cardiac disease of this patient. Patients receiving PPA on a long-term basis should be frequently monitored for cardiac disease, and use of other adrenergic receptor agonists should be avoided in such patients.
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28
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Highly sensitive immunochromatographic assay for qualitative and quantitative control of beta-agonist salbutamol and its structural analogs in foods. Food Control 2018. [DOI: 10.1016/j.foodcont.2017.11.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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29
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Gao J, Li Y, Wang T, Shi Z, Zhang Y, Liu S, Wen P, Ma C. Analyzing gene expression profiles with preliminary validations in cardiac hypertrophy induced by pressure overload. Can J Physiol Pharmacol 2018; 96:701-709. [PMID: 29510080 DOI: 10.1139/cjpp-2017-0585] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The aim of this study was to identify the key genes involved in the cardiac hypertrophy (CH) induced by pressure overload. mRNA microarray data sets GSE5500 and GSE18801 were downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the Limma package; then, functional and pathway enrichment analysis were performed for common DEGs using the Database for Annotation, Visualization and Integrated Discovery database. Furthermore, the top DEGs were further validated using quantitative PCR in the hypertrophic heart tissue induced by isoprenaline. A total of 113 common DEGs with absolute fold change > 0.5, including 60 significantly upregulated DEGs and 53 downregulated DEGs, were obtained. Gene ontology term enrichment analysis suggested that common upregulated DEG were mainly enriched in neutrophil chemotaxis, extracellular fibril organization, and cell proliferation; and the common downregulated genes were significantly enriched in ion transport, endoplasmic reticulum, and dendritic spine. Kyoto Encyclopedia of Genes and Genomes pathway analysis found that the common DEGs were mainly enriched in extracellular matrix receptor interaction, phagosome, and focal adhesion. Additionally, the expression of Mfap4, Ltbp2, Aspn, Serpina3n, and Cnksr1 were upregulated in the model of CH, while the expression of Anp32a was downregulated. The current study identified the key deregulated genes and pathways involved in the CH, which could shed new light to understand the mechanism of CH.
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Affiliation(s)
- Jing Gao
- a Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang 110001, China.,b Department of Ultrasonography, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
| | - Yuhong Li
- b Department of Ultrasonography, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
| | - Tongmei Wang
- c Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Zhuo Shi
- d Department of Anatomy, Jinzhou Medical University, Jinzhou 121001, China
| | - Yiqi Zhang
- c Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Shuang Liu
- a Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang 110001, China
| | - Pushuai Wen
- c Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Chunyan Ma
- a Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang 110001, China
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30
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Schirmer I, Bualeong T, Budde H, Cimiotti D, Appukuttan A, Klein N, Steinwascher P, Reusch P, Mügge A, Meyer R, Ladilov Y, Jaquet K. Soluble adenylyl cyclase: A novel player in cardiac hypertrophy induced by isoprenaline or pressure overload. PLoS One 2018; 13:e0192322. [PMID: 29466442 PMCID: PMC5821345 DOI: 10.1371/journal.pone.0192322] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/22/2018] [Indexed: 12/29/2022] Open
Abstract
Aims In contrast to the membrane bound adenylyl cyclases, the soluble adenylyl cyclase (sAC) is activated by bicarbonate and divalent ions including calcium. sAC is located in the cytosol, nuclei and mitochondria of several tissues including cardiac muscle. However, its role in cardiac pathology is poorly understood. Here we investigate whether sAC is involved in hypertrophic growth using two different model systems. Methods and results In isolated adult rat cardiomyocytes hypertrophy was induced by 24 h β1-adrenoceptor stimulation using isoprenaline (ISO) and a β2-adrenoceptor antagonist (ICI118,551). To monitor hypertrophy cell size along with RNA/DNA- and protein/DNA ratios as well as the expression level of α-skeletal actin were analyzed. sAC activity was suppressed either by treatment with its specific inhibitor KH7 or by knockdown. Both pharmacological inhibition and knockdown blunted hypertrophic growth and reduced expression levels of α-skeletal actin in ISO/ICI treated rat cardiomyocytes. To analyze the underlying cellular mechanism expression levels of phosphorylated CREB, B-Raf and Erk1/2 were examined by western blot. The results suggest the involvement of B-Raf, but not of Erk or CREB in the pro-hypertrophic action of sAC. In wild type and sAC knockout mice pressure overload was induced by transverse aortic constriction. Hemodynamics, heart weight and the expression level of the atrial natriuretic peptide were analyzed. In accordance, transverse aortic constriction failed to induce hypertrophy in sAC knockout mice. Mechanistic analysis revealed a potential role of Erk1/2 in TAC-induced hypertrophy. Conclusion Soluble adenylyl cyclase might be a new pivotal player in the cardiac hypertrophic response either to long-term β1-adrenoceptor stimulation or to pressure overload.
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Affiliation(s)
- Ilona Schirmer
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Tippaporn Bualeong
- Institute of Physiology II, Hospital of the Friedrich-Wilhelms-University of Bonn, Bonn, Germany
| | - Heidi Budde
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Diana Cimiotti
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Avinash Appukuttan
- Clinical Pharmacology, Faculty of Medicine, Ruhr-University of Bochum, Bochum, Germany
| | - Nicole Klein
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Philip Steinwascher
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Peter Reusch
- Clinical Pharmacology, Faculty of Medicine, Ruhr-University of Bochum, Bochum, Germany
| | - Andreas Mügge
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
| | - Rainer Meyer
- Institute of Physiology II, Hospital of the Friedrich-Wilhelms-University of Bonn, Bonn, Germany
| | - Yury Ladilov
- Clinical Pharmacology, Faculty of Medicine, Ruhr-University of Bochum, Bochum, Germany
| | - Kornelia Jaquet
- Cardiology, Research Laboratory Molecular Cardiology, BG Bergmannsheil and St. Josef-Hospital, clinics of the Ruhr-University Bochum, Bochum, Germany
- * E-mail:
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31
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Moura ALD, Hyslop S, Grassi-Kassisse DM, Spadari RC. Functional β2-adrenoceptors in rat left atria: effect of foot-shock stress. Can J Physiol Pharmacol 2017; 95:999-1008. [DOI: 10.1139/cjpp-2016-0622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the β1/β2-adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and β-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective β2-receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective β1-receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that β2-adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.
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Affiliation(s)
- André Luiz de Moura
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil
| | - Stephen Hyslop
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Dora M. Grassi-Kassisse
- Department of Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Regina C. Spadari
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil
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32
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Xu Z, Tong Q, Zhang Z, Wang S, Zheng Y, Liu Q, Qian LB, Chen SY, Sun J, Cai L. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond) 2017; 131:1841-1857. [PMID: 28533215 PMCID: PMC5737625 DOI: 10.1042/cs20170064] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 05/17/2017] [Accepted: 05/19/2017] [Indexed: 02/07/2023]
Abstract
Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevents DCM. Type 1 diabetes OVE26 and age-matched wild-type (WT) mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then killed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice killed immediately or 3 months later following the 3-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation (ChIP) assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. The present study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.
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MESH Headings
- Acrylamides/therapeutic use
- Animals
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/genetics
- Diabetic Cardiomyopathies/etiology
- Diabetic Cardiomyopathies/genetics
- Diabetic Cardiomyopathies/prevention & control
- Drug Evaluation, Preclinical/methods
- Dual-Specificity Phosphatases/metabolism
- Epigenesis, Genetic/drug effects
- Histone Deacetylase Inhibitors/pharmacology
- Histone Deacetylase Inhibitors/therapeutic use
- Histone Deacetylases/drug effects
- Histone Deacetylases/metabolism
- Histone Deacetylases/physiology
- MAP Kinase Signaling System/drug effects
- MAP Kinase Signaling System/genetics
- Male
- Mice, Transgenic
- Myocardium/enzymology
- Oxidative Stress/drug effects
- Phenylenediamines/therapeutic use
- Receptor, Insulin/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Zheng Xu
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
- Pediatric Research Institute at the Department of Pediatrics, the University of Louisville, Louisville, KY 40202, U.S.A
| | - Qian Tong
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Zhiguo Zhang
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Shudong Wang
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Yang Zheng
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Qiuju Liu
- Cancer Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Ling-Bo Qian
- Pediatric Research Institute at the Department of Pediatrics, the University of Louisville, Louisville, KY 40202, U.S.A
- Department of Basic Medical Sciences, Hangzhou Medical College, Hangzhou 310053, China
| | - Shao-Yu Chen
- Department of Pharmacology and Toxicology, Alcohol Research Center, University of Louisville, Louisville, KY 40202, U.S.A
| | - Jian Sun
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Lu Cai
- Cardiovascular Center, the First Hospital of Jilin University, Changchun 130021, China
- Pediatric Research Institute at the Department of Pediatrics, the University of Louisville, Louisville, KY 40202, U.S.A
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33
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Brietz A, Schuch KV, Wangorsch G, Lorenz K, Dandekar T. Analyzing ERK 1/2 signalling and targets. MOLECULAR BIOSYSTEMS 2017; 12:2436-46. [PMID: 27301697 DOI: 10.1039/c6mb00255b] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The ERK cascade (e.g. Raf-1) protects the heart from cell death and ischemic injury but can also turn maladaptive. Furthermore, an additional autophosphorylation of ERK2 at Thr188 (Erk1 at Thr208) allows ERK to phosphorylate nuclear targets involved in hypertrophy, stressing this additional phosphorylation as a promising pharmacological target. An in silico model was assembled and setup to reproduce different phosphorylation states of ERK 1/2 and various types of stimuli (hypertrophic versus non-hypertrophic). Synergistic and antagonistic receptor stimuli can be predicted in a semi-quantitative model, simulated time courses were experimentally validated. Furthermore, we detected new targets of ERK 1/2, which possibly contribute to the development of pathological hypertrophy. In addition we modeled further interaction partners involved in the protective and maladaptive cascade. Experimental validation included different gene expression data sets supporting key components and novel interaction partners as well as time courses in chronic heart failure.
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Affiliation(s)
- Alexandra Brietz
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
| | | | - Gaby Wangorsch
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
| | - Kristina Lorenz
- Biomedizinsche Forschung, Leibniz Institut für Analytische Wissenschaften - ISAS - e.V, Bunsen-Kirchhoff Straße 11, 44139 Dortmund, Germany and West German Heart and Vascular Center Essen, University Hospital Essen-Duisburg, Duisburg, Germany
| | - Thomas Dandekar
- Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
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34
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Qiao Y, Zhu B, Tian A, Li Z. PEG-coated gold nanoparticles attenuate β-adrenergic receptor-mediated cardiac hypertrophy. Int J Nanomedicine 2017; 12:4709-4719. [PMID: 28740379 PMCID: PMC5503492 DOI: 10.2147/ijn.s130951] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Gold nanoparticles (AuNPs) are widely used as a drug delivery vehicle, which can accumulate in the heart through blood circulation. Therefore, it is very important to understand the effect of AuNPs on the heart, especially under pathological conditions. In this study, we found that PEG-coated AuNPs attenuate β-adrenergic receptor (β-AR)-mediated acute cardiac hypertrophy and inflammation. However, both isoproterenol, a non-selective β-AR agonist, and AuNPs did not induce cardiac function change or cardiac fibrosis. AuNPs exerted an anti-cardiac hypertrophy effect by decreasing β1-AR expression and its downstream ERK1/2 hypertrophic pathway. Our results indicated that AuNPs might be safe and have the potential to be used as multi-functional materials (drug carrier systems and anti-cardiac hypertrophy agents).
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Affiliation(s)
- Yuhui Qiao
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, People's Republic of China
| | - Baoling Zhu
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, People's Republic of China
| | - Aiju Tian
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, People's Republic of China
| | - Zijian Li
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, People's Republic of China
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35
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Lorenz K, Rosner MR, Brand T, Schmitt JP. Raf kinase inhibitor protein: lessons of a better way for β-adrenergic receptor activation in the heart. J Physiol 2017; 595:4073-4087. [PMID: 28444807 PMCID: PMC5471367 DOI: 10.1113/jp274064] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 02/27/2017] [Indexed: 12/13/2022] Open
Abstract
Stimulation of β-adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight-or-flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long-term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP-driven compared to receptor-mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on β1 - and β2 -ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.
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Affiliation(s)
- Kristina Lorenz
- Comprehensive Heart Failure CenterUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
- West German Heart and Vascular Center EssenUniversity Hospital EssenHufelandstraße 5545147EssenGermany
- Leibniz‐Institut für Analytische Wissenschaften – ISAS – e.V.Bunsen‐Kirchhoff‐Straße 1144139DortmundGermany
- Institute of Pharmacology and ToxicologyUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
| | - Marsha Rich Rosner
- Ben May Department for Cancer ResearchUniversity of ChicagoChicagoIL 60637USA
| | - Theresa Brand
- Leibniz‐Institut für Analytische Wissenschaften – ISAS – e.V.Bunsen‐Kirchhoff‐Straße 1144139DortmundGermany
- Institute of Pharmacology and ToxicologyUniversity of WürzburgVersbacher Straße 997078WürzburgGermany
| | - Joachim P Schmitt
- Institute of Pharmacology and Clinical PharmacologyDüsseldorf University HospitalUniverstitätsstraße 140225DüsseldorfGermany
- Cardiovascular Research Institute Düsseldorf (CARID)Heinrich‐Heine‐UniversityUniverstitätsstraße 140225DüsseldorfGermany
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36
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Fu Q, Wang Q, Xiang YK. Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart. Trends Endocrinol Metab 2017; 28:416-427. [PMID: 28256297 PMCID: PMC5535765 DOI: 10.1016/j.tem.2017.02.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 01/29/2017] [Accepted: 02/01/2017] [Indexed: 02/03/2023]
Abstract
Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in the heart to modulate cardiac function in clinically relevant states, such as diabetes mellitus (DM) and heart failure (HF). Conversely, activation of βAR regulates cardiac glucose uptake and promotes insulin resistance (IR) in HF. Here, we discuss the recent characterization of the interaction between the cardiac insulin receptor (InsR) and βAR in the myocardium, in which insulin stimulation crosstalks with cardiac βAR via InsR substrate (IRS)-dependent and G-protein receptor kinase 2 (GRK2)-mediated phosphorylation of β2AR. The insulin-induced phosphorylation promotes β2AR coupling to Gi and expression of phosphodiesterase 4D, which both inhibit cardiac adrenergic signaling and compromise cardiac contractile function. These recent developments could support new approaches for the effective prevention or treatment of obesity- or DM-related HF.
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Affiliation(s)
- Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China.
| | - Qingtong Wang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, China.
| | - Yang K Xiang
- Department of Pharmacology, University of California, Davis, CA, USA; VA Northern California Health Care System, Mather, CA, USA.
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37
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Tur J, Chapalamadugu KC, Katnik C, Cuevas J, Bhatnagar A, Tipparaju SM. Kvβ1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity. Am J Physiol Heart Circ Physiol 2016; 312:H571-H583. [PMID: 27986658 PMCID: PMC5402009 DOI: 10.1152/ajpheart.00281.2016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 11/28/2016] [Accepted: 12/12/2016] [Indexed: 12/19/2022]
Abstract
The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvβ1.1 knockout (KO) or wild-type (WT) mice and established that Kvβ1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvβ1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvβ1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvβ1.1 is required in the mediated inactivation of Kv4.2 currents, when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in wild-type mice; regardless of the approach, our data show that Kvβ1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart.NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvβ1.1 subunit. In the present study, we identify Kvβ1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart.
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Affiliation(s)
- Jared Tur
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida.,Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Kalyan C Chapalamadugu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida
| | - Christopher Katnik
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida; and
| | - Javier Cuevas
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida; and
| | - Aruni Bhatnagar
- Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky
| | - Srinivas M Tipparaju
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida;
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38
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Xu Z, Sun J, Tong Q, Lin Q, Qian L, Park Y, Zheng Y. The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy. Int J Mol Sci 2016; 17:2001. [PMID: 27941647 PMCID: PMC5187801 DOI: 10.3390/ijms17122001] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/14/2016] [Accepted: 11/22/2016] [Indexed: 12/23/2022] Open
Abstract
Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on "differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury".
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Affiliation(s)
- Zheng Xu
- Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China.
- Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY 40202, USA.
| | - Jian Sun
- Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China.
| | - Qian Tong
- Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China.
| | - Qian Lin
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA.
| | - Lingbo Qian
- Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY 40202, USA.
- Department of Basic Medical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
| | - Yongsoo Park
- Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY 40202, USA.
- College of Medicine & Engineering, Hanyang University, Seoul 04963, Korea.
| | - Yang Zheng
- Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China.
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39
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Kulikovskii AV, Lisitsyn AB, Gorlov IF, Slozhenkina MI, Savchuk SA. Determination of growth hormones (β-agonists) in muscle tissue by HPLC with mass spectrometric detection. JOURNAL OF ANALYTICAL CHEMISTRY 2016. [DOI: 10.1134/s1061934816100075] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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40
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Lou J, Zhao D, Zhang LL, Song SY, Li YC, Sun F, Ding XQ, Yu CJ, Li YY, Liu MT, Dong CJ, Ji Y, Li H, Chu W, Zhang ZR. Type III Transforming Growth Factor-β Receptor Drives Cardiac Hypertrophy Through β-Arrestin2–Dependent Activation of Calmodulin-Dependent Protein Kinase II. Hypertension 2016; 68:654-66. [PMID: 27432858 DOI: 10.1161/hypertensionaha.116.07420] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/22/2016] [Indexed: 01/02/2023]
Abstract
The role of type III transforming growth factor-β receptor (TβRIII) in the pathogenesis of heart diseases remains largely unclear. Here, we investigated the functional role and molecular mechanisms of TβRIII in the development of myocardial hypertrophy. Western blot and quantitative real time-polymerase chain reaction analyses revealed that the expression of TβRIII was significantly elevated in human cardiac hypertrophic samples. Consistently, TβRIII expression was substantially increased in transverse aortic constriction (TAC)– and isoproterenol-induced mouse cardiac hypertrophy in vivo and in isoproterenol-induced cardiomyocyte hypertrophy in vitro. Overexpression of TβRIII resulted in cardiomyocyte hypertrophy, whereas isoproterenol-induced cardiomyocyte hypertrophy was greatly attenuated by knockdown of TβRIII in vitro. Cardiac-specific transgenic expression of TβRIII independently led to cardiac hypertrophy in mice, which was further aggravated by isoproterenol and TAC treatment. Cardiac contractile function of the mice was not altered in TβRIII transgenic mice; however, TAC led to significantly decreased cardiac contractile function in TβRIII transgenic mice compared with control mice. Conversely, isoproterenol- and TAC-induced cardiac hypertrophy and TAC-induced cardiac contractile function impairment were partially reversed by suppression of TβRIII in vivo. Our data suggest that TβRIII mediates stress-induced cardiac hypertrophy through activation of Ca
2+
/calmodulin-dependent protein kinase II, which requires a physical interaction of β-arrestin2 with both TβRIII and calmodulin-dependent protein kinase II. Our findings indicate that stress-induced increase in TβRIII expression results in cardiac hypertrophy through β-arrestin2–dependent activation of calmodulin-dependent protein kinase II and that transforming growth factor-β and β-adrenergic receptor signaling are not involved in spontaneous cardiac hypertrophy in cardiac-specific transgenic expression of TβRIII mice. Our findings may provide a novel target for control of myocardial hypertrophy.
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Affiliation(s)
- Jie Lou
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Dan Zhao
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
| | - Ling-Ling Zhang
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Shu-Ying Song
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Yan-Chao Li
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Fei Sun
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Xiao-Qing Ding
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Chang-Jiang Yu
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Yuan-Yuan Li
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Mei-Tong Liu
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Chang-Jiang Dong
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Yong Ji
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Hongliang Li
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.)
| | - Wenfeng Chu
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
| | - Zhi-Ren Zhang
- From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
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Li C, Chen Z, Yang H, Luo F, Chen L, Cai H, Li Y, You G, Long D, Li S, Zhang Q, Rao L. Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway. PLoS One 2016; 11:e0159079. [PMID: 27438013 PMCID: PMC4954659 DOI: 10.1371/journal.pone.0159079] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 06/27/2016] [Indexed: 02/05/2023] Open
Abstract
Aims Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. Methods and Results In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Conclusions Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials.
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Affiliation(s)
- Chen Li
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zhongxiu Chen
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hao Yang
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Fangbo Luo
- Department of Rehabilitation, Community Health Center of Shuangnan Wuhou District, Chengdu, Sichuan, China
| | - Lihong Chen
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Huawei Cai
- Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yajiao Li
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Guiying You
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dan Long
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital of Sichuan University, High-tech Zone, Chengdu, Sichuan, China
| | - Shengfu Li
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital of Sichuan University, High-tech Zone, Chengdu, Sichuan, China
| | - Qiuping Zhang
- King’s College London British Heart Foundation Centre of Research Excellence, Cardiovascular Division, London, United Kingdom
| | - Li Rao
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- * E-mail:
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42
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Gβγ subunits-Different spaces, different faces. Pharmacol Res 2016; 111:434-441. [PMID: 27378564 DOI: 10.1016/j.phrs.2016.06.026] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 06/27/2016] [Accepted: 06/28/2016] [Indexed: 11/20/2022]
Abstract
Gβγ subunits play key roles in modulation of canonical effectors in G protein-coupled receptor (GPCR)-dependent signalling at the cell surface. However, a number of recent studies of Gβγ function have revealed that they regulate a large number of molecules at distinct subcellular sites. These novel, non-canonical Gβγ roles have reshaped our understanding of how important Gβγ signalling is compared to our original notion of Gβγ subunits as simple negative regulators of Gα subunits. Gβγ dimers have now been identified as regulators of transcription, anterograde and retrograde trafficking and modulators of second messenger molecule generation in intracellular organelles. Here, we review some recent advances in our understanding of these novel non-canonical roles of Gβγ.
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43
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Propping S, Lorenz K, Michel MC, Wirth MP, Ravens U. β-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in β2-Adrenoceptor Knockout Mice. Front Pharmacol 2016; 7:118. [PMID: 27242525 PMCID: PMC4860462 DOI: 10.3389/fphar.2016.00118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 04/22/2016] [Indexed: 11/13/2022] Open
Abstract
Background and Objective: In order to characterize the β-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and β2-AR knockout (β2-AR KO) mice. Materials and Methods: Urinary bladders were isolated from male WT and β2-AR KO mice. β-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or β3-AR agonist CL 316,243 in the presence and absence of the subtype-selective β-AR blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Results: Quantitative real-time PCR confirmed lack of β2-AR expression in bladder tissue from β2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in β2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in β2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 μM). The -logEC50 values for (-)-isoprenaline in WT and β2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of β2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and β2-AR KO mice with a potency corresponding to the drug’s affinity for β3-AR. L743,337 shifted the CRCs to the right. Conclusion: Our findings in β2-AR KO mice suggest that there is a large receptor reserve for β2-AR in WT mice so that this β-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, β3-AR can also mediate murine detrusor relaxation.
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Affiliation(s)
- Stefan Propping
- Department of Urology, Faculty of Medicine Carl Gustav Carus, Dresden University of TechnologyDresden, Germany; Department of Physiology, Faculty of Medicine Carl Gustav Carus, Dresden University of TechnologyDresden, Germany
| | - Kristina Lorenz
- Department of Pharmacology and Toxicology, Julius Maximilian University WürzburgWürzburg, Germany; Leibniz-Institute für Analytische Wissenschaften-ISAS-e.V.Dortmund, Germany; West German Heart and Vascular Center Essen, University Hospital Essen-DuisburgDuisburg, Germany
| | - Martin C Michel
- Department of Pharmacology, Johannes Gutenberg University Mainz, Germany
| | - Manfred P Wirth
- Department of Urology, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology Dresden, Germany
| | - Ursula Ravens
- Department of Physiology, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology Dresden, Germany
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44
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Yu LM, Xu Y. Epigenetic regulation in cardiac fibrosis. World J Cardiol 2015; 7:784-791. [PMID: 26635926 PMCID: PMC4660473 DOI: 10.4330/wjc.v7.i11.784] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/16/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this mini-review, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs.
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45
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Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, Deiss K, Denzinger S, Herrmann S, Wettwer E, Weidendorfer M, Becker D, Schäfer F, Wagner N, Ergün S, Schmitt JP, Katus HA, Weidemann F, Ravens U, Maack C, Hein L, Ertl G, Müller OJ, Maier LS, Lohse MJ, Lorenz K. Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy. Nat Med 2015; 21:1298-306. [PMID: 26479924 DOI: 10.1038/nm.3972] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/12/2015] [Indexed: 01/08/2023]
Abstract
In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.
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Affiliation(s)
- Evelyn Schmid
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Stefan Neef
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Christopher Berlin
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Angela Tomasovic
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Katrin Kahlert
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Peter Nordbeck
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Katharina Deiss
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Sabrina Denzinger
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Sebastian Herrmann
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Erich Wettwer
- Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Markus Weidendorfer
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Daniel Becker
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Florian Schäfer
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Nicole Wagner
- Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Joachim P Schmitt
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany
| | - Hugo A Katus
- Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.,German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany
| | - Frank Weidemann
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Ursula Ravens
- Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Christoph Maack
- Clinic for Internal Medicine III, Saarland University Hospital, Homburg, Germany
| | - Lutz Hein
- Institute of Experimental and Clinical Pharmacology and Toxicology, Freiburg, Germany.,Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
| | - Georg Ertl
- Comprehensive Heart Failure Center, Würzburg, Germany.,Department of Internal Medicine I, University of Würzburg, Würzburg, Germany
| | - Oliver J Müller
- Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.,German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Martin J Lohse
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.,Comprehensive Heart Failure Center, Würzburg, Germany
| | - Kristina Lorenz
- Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.,Comprehensive Heart Failure Center, Würzburg, Germany
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46
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Birket MJ, Ribeiro MC, Kosmidis G, Ward D, Leitoguinho AR, van de Pol V, Dambrot C, Devalla HD, Davis RP, Mastroberardino PG, Atsma DE, Passier R, Mummery CL. Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function. Cell Rep 2015; 13:733-745. [PMID: 26489474 PMCID: PMC4644234 DOI: 10.1016/j.celrep.2015.09.025] [Citation(s) in RCA: 147] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/31/2015] [Accepted: 09/05/2015] [Indexed: 12/23/2022] Open
Abstract
Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.
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Affiliation(s)
- Matthew J Birket
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Marcelo C Ribeiro
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Georgios Kosmidis
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Dorien Ward
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Ana Rita Leitoguinho
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Vera van de Pol
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Cheryl Dambrot
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Harsha D Devalla
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Richard P Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | | | - Douwe E Atsma
- Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Robert Passier
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
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Somatostatin activates Ras and ERK1/2 via a G protein βγ-subunit-initiated pathway in thyroid cells. Mol Cell Biochem 2015; 411:253-60. [PMID: 26472731 DOI: 10.1007/s11010-015-2587-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 10/08/2015] [Indexed: 10/22/2022]
Abstract
Somatostatin (SST) is one of the main regulators of thyroid function. It acts by binding to its receptors, which lead to the dissociation of G proteins into Gαi and Gβγ subunits. However, much less is known about the function of Gβγ in thyroid cells. Here, we studied the role of SST and Gβγ dimers released upon SST stimulation on the Ras-ERK1/2 pathway in FTRL-5 thyroid cells. We demonstrate that SST activates Ras through Gi proteins, since SST-induced Ras activation is inhibited by pertussis toxin. Moreover, the specific sequestration of Gβγ dimers decreases Ras-GTP and phosphorylated ERK1/2 levels, and overexpression of Gβγ increases ERK1/2 phosphorylation induced by SST, indicating that Gβγ dimers released after SST treatment mediate activation of Ras and ERK1/2. On the other hand, SST treatment does not modify the expression of the thyroid differentiation marker sodium/iodide symporter (NIS) through ERK1/2 activation. However, SST increases AKT activation and the inhibition of the Src/PI3K/AKT pathway increases NIS levels in SST-treated cells. Thus, we conclude that, in thyroid cells, signalling from SST receptors to ERK1/2 involves a Gβγ-mediated signal acting on a Ras-dependent pathway. Moreover, we demonstrate that SST might regulates NIS expression through a Src/PI3K/AKT-dependent mechanism, but not through ERK1/2 signalling, showing the main role of this hormone in thyroid function.
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48
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Abstract
The small HSP (heat-shock protein) HSP20 is a molecular chaperone that is transiently up-regulated in response to cellular stress/damage. Although ubiquitously expressed in various tissues, it is most highly expressed in skeletal, cardiac and smooth muscle. Phosphorylation at Ser16 by PKA (cAMP-dependent protein kinase) is essential for HSP20 to confer its protective qualities. HSP20 and its phosphorylation have been implicated in a variety of pathophysiological processes, but most prominently cardiovascular disease. A wealth of knowledge of the importance of HSP20 in contractile function and cardioprotection has been gained over the last decade. The present mini-review highlights more recent findings illustrating the cardioprotective properties of HSP20 and its potential as a therapeutic agent.
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49
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Alleman RJ, Stewart LM, Tsang AM, Brown DA. Why Does Exercise "Trigger" Adaptive Protective Responses in the Heart? Dose Response 2015; 13:10.2203_dose-response.14-023.Alleman. [PMID: 26674259 PMCID: PMC4674163 DOI: 10.2203/dose-response.14-023.alleman] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Numerous epidemiological studies suggest that individuals who exercise have decreased cardiac morbidity and mortality. Pre-clinical studies in animal models also find clear cardioprotective phenotypes in animals that exercise, specifically characterized by lower myocardial infarction and arrhythmia. Despite the clear benefits, the underlying cellular and molecular mechanisms that are responsible for exercise preconditioning are not fully understood. In particular, the adaptive signaling events that occur during exercise to "trigger" cardioprotection represent emerging paradigms. In this review, we discuss recent studies that have identified several different factors that appear to initiate exercise preconditioning. We summarize the evidence for and against specific cellular factors in triggering exercise adaptations and identify areas for future study.
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Affiliation(s)
- Rick J Alleman
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville NC USA
| | - Luke M Stewart
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville NC USA
| | - Alvin M Tsang
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville NC USA
| | - David A Brown
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville NC USA
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50
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Park G, Yoon BS, Kim YS, Choi SC, Moon JH, Kwon S, Hwang J, Yun W, Kim JH, Park CY, Lim DS, Kim YI, Oh CH, You S. Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. Biomaterials 2015; 54:201-12. [PMID: 25907053 DOI: 10.1016/j.biomaterials.2015.02.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/02/2015] [Indexed: 12/13/2022]
Abstract
The possibility of controlling cell fates by overexpressing specific transcription factors has led to numerous studies in stem cell research. Small molecules can be used, instead of transcription factors, to induce the de-differentiation of somatic cells or to induce pluripotent cells (iPSCs). Here we reported that combinations of small molecules could convert mouse fibroblasts into cardiomyocyte-like cell without requiring transcription factor expression. Treatment with specific combinations of small molecules that are enhancer for iPSC induction converted mouse fibroblasts into spontaneously contracting, cardiac troponin T-positive, cardiomyocyte-like cells. We specifically identified five small molecules that can induce mouse fibroblasts to form these cardiomyocyte-like cells. These cells are similar to primary cardiomyocytes in terms of marker gene expression, epigenetic status of cardiac-specific genes, and subcellular structure. Our findings indicate that lineage conversion can be induced not only by transcription factors, but also by small molecules.
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Affiliation(s)
- Gyuman Park
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Byung Sun Yoon
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Yoon Sik Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seung-Cheol Choi
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Jai-Hee Moon
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Suhyun Kwon
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jihye Hwang
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Wonjin Yun
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jong-Ho Kim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Chi-Yeon Park
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Do-Sun Lim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Yang In Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, Seoul, Republic of Korea
| | - Chil Hwan Oh
- Department of Dermatology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
| | - Seungkwon You
- Laboratory of Cell Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
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