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Lai Y, Tang Z, Du Z, Zeng Q, Xia Y, Chen S, Li X, Cheng Q, Mei M, He W. Attenuation of Hypertension and protection of vascular inflammation in hyperaldosteronism: GPER1 as potential therapeutic candidate when MR antagonist is less satisfying? Endocrine 2025; 87:1276-1284. [PMID: 39565544 PMCID: PMC11845544 DOI: 10.1007/s12020-024-04106-6] [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: 08/20/2024] [Accepted: 11/07/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Hyperaldosteronism is an endocrine disorder leading to persistent and severe hypertension. G protein-coupled estrogen receptor 1(GPER1) is regarded as a potential receptor of aldosterone (ALDO). OBJECTIVE This study aimed to investigate the effects of GPER1 on aldosterone (ALDO)-induced hypertension and inflammation in mice. METHODS GPER1-knockout (KO) and wild-type (WT) C57BL/6j mice were divided into control (CON, normal saline treatment), ALDO (subcutaneous injections of 600 g/kg/d ALDO), and ALDO + eplerenone (EPL) (subcutaneous injections of 600 g/kg/d ALDO and 100 mg/kg/d EPL) groups (n = 5 per group). Fourteen days after drug administration, the heart rate and tail blood pressure of the mice in the different groups were measured. S100A8 and IL-1β protein expression in arterial tissues were detected by western blotting, NLRP3 expression was assessed using immunofluorescence, and CD68 expression was investigated using immunohistochemistry. RESULTS GPER1 deficiency alleviated ALDO-induced diastolic blood pressure (P< 0.05). In addition, the protein expression levels of IL-1β, S100A8, and CD68 showed significant decreases in the arterial tissues of GPER1-KO mice after combination treatment with ALDO and EPL (all P < 0.05). CONCLUSION We discovered attenuation of hypertension and vascular inflammation of GPER1 KO mice only on the basis of mineralocorticoid receptor (MR) blocking. Collectively, our study indicates that GPER1 might become a therapeutic target of hyperaldosteronism in controlling the residual risk of cardiovascular disease when MR antagonist alone is not satisfying.
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Affiliation(s)
- Yulian Lai
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ziwei Tang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Zhipeng Du
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qinglian Zeng
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Xia
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shangbin Chen
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xun Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qingfeng Cheng
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mei Mei
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenwen He
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Kaplan A, El‐Samadi L, Zahreddine R, Amin G, Booz GW, Zouein FA. Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure. Acta Physiol (Oxf) 2025; 241:e70010. [PMID: 39960030 PMCID: PMC11831727 DOI: 10.1111/apha.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/20/2025]
Abstract
G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Cardiology ClinicKemer Public HospitalAntalyaTurkey
| | - Lana El‐Samadi
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Rana Zahreddine
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Ghadir Amin
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Fouad A. Zouein
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
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Biswal N, Harish R, Roshan M, Samudrala S, Jiao X, Pestell RG, Ashton AW. Role of GPCR Signaling in Anthracycline-Induced Cardiotoxicity. Cells 2025; 14:169. [PMID: 39936961 PMCID: PMC11817789 DOI: 10.3390/cells14030169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/27/2024] [Accepted: 11/27/2024] [Indexed: 02/13/2025] Open
Abstract
Anthracyclines are a class of chemotherapeutics commonly used to treat a range of cancers. Despite success in improving cancer survival rates, anthracyclines have dose-limiting cardiotoxicity that prevents more widespread clinical utility. Currently, the therapeutic options for these patients are limited to the iron-chelating agent dexrazoxane, the only FDA-approved drug for anthracycline cardiotoxicity. However, the clinical use of dexrazoxane has failed to replicate expectations from preclinical studies. A limited list of GPCRs have been identified as pathogenic in anthracycline-induced cardiotoxicity, including receptors (frizzled, adrenoreceptors, angiotensin II receptors) previously implicated in cardiac remodeling in other pathologies. The RNA sequencing of iPSC-derived cardiac myocytes from patients has increased our understanding of the pathogenic mechanisms driving cardiotoxicity. These data identified changes in the expression of novel GPCRs, heterotrimeric G proteins, and the regulatory pathways that govern downstream signaling. This review will capitalize on insights from these experiments to explain aspects of disease pathogenesis and cardiac remodeling. These data provide a cornucopia of possible unexplored potential pathways by which we can reduce the cardiotoxic side effects, without compromising the anti-cancer effects, of doxorubicin and provide new therapeutic options to improve the recovery and quality of life for patients undergoing chemotherapy.
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Affiliation(s)
- Nimish Biswal
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Ritika Harish
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Minahil Roshan
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Sathvik Samudrala
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Xuanmao Jiao
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Richard G. Pestell
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- The Wistar Institute, Philadelphia, PA 19104, USA
| | - Anthony W. Ashton
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- Division of Perinatal Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW 2065, Australia
- Division of Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
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Wang J, Xue H, He J, Deng L, Tian J, Jiang Y, Feng J. Therapeutic potential of finerenone for diabetic cardiomyopathy: focus on the mechanisms. Diabetol Metab Syndr 2024; 16:232. [PMID: 39289758 PMCID: PMC11409712 DOI: 10.1186/s13098-024-01466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/06/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a kind of myocardial disease that occurs in diabetes patients and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease and other heart diseases. Its pathogenesis may be closely related to programmed cell death, oxidative stress, intestinal microbes and micro-RNAs. The excessive activation of mineralocorticoid receptors (MR) in DCM can cause damage to the heart and kidneys. The third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone, can effectively block MR, thus playing a role in protecting the heart and kidneys. This review mainly introduces the classification of MRA, and the mechanism of action, applications and limitations of finerenone in DCM, in order to provide reference for the study of treatment plans for DCM patients.
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Affiliation(s)
- Jing Wang
- Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People's Hospital), Luzhou, Sichuan, China
| | - Haojie Xue
- Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People's Hospital), Luzhou, Sichuan, China
| | - Jinyu He
- Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People's Hospital), Luzhou, Sichuan, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Julong Tian
- Department of Cardiology, The Affiliated Hospital of Panzhihua University, Panzhihua, Sichuan, China
| | - Yang Jiang
- Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People's Hospital), Luzhou, Sichuan, China.
| | - Jian Feng
- Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People's Hospital), Luzhou, Sichuan, China.
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Vecchiola A, Uslar T, Friedrich I, Aguirre J, Sandoval A, Carvajal CA, Tapia-Castillo A, Martínez-García A, Fardella CE. The role of sex hormones in aldosterone biosynthesis and their potential impact on its mineralocorticoid receptor. Cardiovasc Endocrinol Metab 2024; 13:e0305. [PMID: 38846628 PMCID: PMC11155591 DOI: 10.1097/xce.0000000000000305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 04/22/2024] [Indexed: 06/09/2024]
Abstract
Blood pressure (BP) regulation is a complex process involving various hormones, including aldosterone and its mineralocorticoid receptor. Mineralocorticoid receptor is expressed in several tissues, including the kidney, and plays a crucial role in regulating BP by controlling the sodium and water balance. During different stages of life, hormonal changes can affect mineralocorticoid receptor activity and aldosterone levels, leading to changes in BP. Increasing evidence suggests that sex steroids modulate aldosterone levels. Estrogens, particularly estradiol, mediate aldosterone biosynthesis by activating classical estrogen receptors and the G protein-coupled receptor. Progesterone acts as an anti-mineralocorticoid by inhibiting the binding of aldosterone to the mineralocorticoid receptor. Moreover, progesterone inhibits aldosterone synthase enzymes. The effect of testosterone on aldosterone synthesis is still a subject of debate. However, certain studies show that testosterone downregulates the mRNA levels of aldosterone synthase, leading to decreased plasma aldosterone levels.
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Affiliation(s)
- Andrea Vecchiola
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
| | - Thomas Uslar
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
| | - Isidora Friedrich
- Departamento de Endocrinologìa, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago
| | - Joaquin Aguirre
- Departamento de Endocrinologìa, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago
| | - Alejandra Sandoval
- Escuela de Tecnología Médica, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Cristian A. Carvajal
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
| | - Alejandra Tapia-Castillo
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
| | - Alejandra Martínez-García
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
| | - Carlos E. Fardella
- Departamento de Endocrinología, Facultad de Medicina, Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Católica de Chile
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Nagliya D, Baggio Lopez T, Del Calvo G, Stoicovy RA, Borges JI, Suster MS, Lymperopoulos A. Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α 2-Adrenergic Receptors in PC12 Cells. Int J Mol Sci 2024; 25:5227. [PMID: 38791266 PMCID: PMC11120680 DOI: 10.3390/ijms25105227] [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: 03/23/2024] [Revised: 04/29/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.
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Affiliation(s)
| | | | | | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (D.N.); (T.B.L.); (G.D.C.); (R.A.S.); (J.I.B.); (M.S.S.)
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Rendell M. Lessons learned from early-stage clinical trials for diabetic nephropathy. Expert Opin Investig Drugs 2024; 33:287-301. [PMID: 38465470 DOI: 10.1080/13543784.2024.2326025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 02/28/2024] [Indexed: 03/12/2024]
Abstract
INTRODUCTION The evolution of treatment for diabetic nephropathy illustrates how basic biochemistry and physiology have led to new agents such as SGLT2 inhibitors and mineralocorticoid blockers. Conversely, clinical studies performed with these agents have suggested new concepts for investigational drug development. We reviewed currently available treatments for diabetic nephropathy and then analyzed early clinical trials of new agents to assess the potential for future treatment modalities. AREAS COVERED We searched ClinicalTrials.gov for new agents under study for diabetic nephropathy in the past decade. Once we have identified investigation trials of new agents, we then used search engines and Pubmed.gov to find publications providing insight on these drugs. Current treatments have shown benefit in both cardiac and renal disease. In our review, we found 51 trials and 43 pharmaceuticals in a number of drug classes: mineralocorticoid blockers, anti-inflammatory, anti-fibrosis, nitric oxide stimulatory, and podocyte protection, and endothelin inhibitors. EXPERT OPINION It is difficult to predict which early phase treatments will advance to confirmatory clinical trials. Current agents are thought to improve hemodynamic function. However, the coincident benefit of both myocardial function and the glomerulus argues for primary effects at the subcellular level, and we follow the evolution of agents which modify fundamental cellular processes.
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Affiliation(s)
- Marc Rendell
- The Association of Diabetes Investigators, Newport Coast, CA, USA
- The Rose Salter Medical Research Foundation, Newport Coast, CA, USA
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Salgado Rezende de Mendonça L, Senar S, Moreira LL, Silva Júnior JA, Nader M, Campos LA, Baltatu OC. Evidence for the druggability of aldosterone targets in heart failure: A bioinformatics and data science-driven decision-making approach. Comput Biol Med 2024; 171:108124. [PMID: 38412691 DOI: 10.1016/j.compbiomed.2024.108124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 02/02/2024] [Accepted: 02/05/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND Aldosterone plays a key role in the neurohormonal drive of heart failure. Systematic prioritization of drug targets using bioinformatics and database-driven decision-making can provide a competitive advantage in therapeutic R&D. This study investigated the evidence on the druggability of these aldosterone targets in heart failure. METHODS The target disease predictability of mineralocorticoid receptors (MR) and aldosterone synthase (AS) in cardiac failure was evaluated using Open Targets target-disease association scores. The Open Targets database collections were downloaded to MongoDB and queried according to the desired aggregation level, and the results were retrieved from the Europe PMC (data type: text mining), ChEMBL (data type: drugs), Open Targets Genetics Portal (data type: genetic associations), and IMPC (data type: genetic associations) databases. The target tractability of MR and AS in the cardiovascular system was investigated by computing activity scores in a curated ChEMBL database using supervised machine learning. RESULTS The medians of the association scores of the MR and AS groups were similar, indicating a comparable predictability of the target disease. The median of the MR activity scores group was significantly lower than that of AS, indicating that AS has higher target tractability than MR [Hodges-Lehmann difference 0.62 (95%CI 0.53-0.70, p < 0.0001]. The cumulative distributions of the overall multiplatform association scores of cardiac diseases with MR were considerably higher than with AS, indicating more advanced investigations on a wider range of disorders evaluated for MR (Kolmogorov-Smirnov D = 0.36, p = 0.0009). In curated ChEMBL, MR had a higher cumulative distribution of activity scores in experimental cardiovascular assays than AS (Kolmogorov-Smirnov D = 0.23, p < 0.0001). Documented clinical trials for MR in heart failures surfaced in database searches, none for AS. CONCLUSIONS Although its clinical development has lagged behind that of MR, our findings indicate that AS is a promising therapeutic target for the treatment of cardiac failure. The multiplatform-integrated identification used in this study allowed us to comprehensively explore the available scientific evidence on MR and AS for heart failure therapy.
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Affiliation(s)
- Lucas Salgado Rezende de Mendonça
- Center of Innovation, Technology, and Education (CITE) at Anhembi Morumbi University, Anima Institute, Sao Jose dos Campos Technology Park, Sao Jose dos Campos, Brazil
| | | | - Luana Lorena Moreira
- Center of Innovation, Technology, and Education (CITE) at Anhembi Morumbi University, Anima Institute, Sao Jose dos Campos Technology Park, Sao Jose dos Campos, Brazil
| | | | - Moni Nader
- College of Medicine & Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Luciana Aparecida Campos
- Center of Innovation, Technology, and Education (CITE) at Anhembi Morumbi University, Anima Institute, Sao Jose dos Campos Technology Park, Sao Jose dos Campos, Brazil.
| | - Ovidiu Constantin Baltatu
- Center of Innovation, Technology, and Education (CITE) at Anhembi Morumbi University, Anima Institute, Sao Jose dos Campos Technology Park, Sao Jose dos Campos, Brazil.
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Chen IS, Yasuda J, Notomi T, Nakamura TY. Licorice metabolite 18β-glycyrrhetinic acid activates G protein-gated inwardly rectifying K + channels. Br J Pharmacol 2024; 181:447-463. [PMID: 37642133 DOI: 10.1111/bph.16228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND AND PURPOSE Licorice (liquorice) is a common food additive and is used in Chinese medicine. Excess licorice intake can induce atrial fibrillation. Patients with atrial fibrillation possess constitutively activated G protein-gated inwardly rectifying K+ (GIRK) channels. Whether licorice affects GIRK channel activity is unknown. We aimed to clarify the effects of licorice ingredients on GIRK current and the mechanism of action. EXPERIMENTAL APPROACH A major component of licorice, glycyrrhizic acid (GA), and its metabolite, 18β-glycyrrhetinic acid (18β-GA), were tested. We performed electrophysiological recordings in Xenopus oocytes to examine the effects of GA and 18β-GA on various GIRK subunits (Kir 3.1-Kir 3.4), mutagenesis analyses to identify the crucial residues for drug action and motion analysis in cultured rat atrial myocytes to clarify effects of 18β-GA on atrial functions. KEY RESULTS GA inhibited Kir 3.1-containing channels, while 18β-GA activated all Kir 3.x subunits. A pore helix residue Phe137 in Kir 3.1 was critical for GA-mediated inhibition, and the corresponding Ser148 in Kir 3.2 was critical for 18β-GA-mediated activation. 18β-GA activated GIRK channel in a Gβγ -independent manner, whereas phosphatidylinositol 4,5-bisphosphate (PIP2 ) was essential for activation. Glu236 located at the cytoplasmic pore of Kir 3.2 appeared to be important to interactions with 18β-GA. In rat atrial myocytes, 18β-GA suppressed spontaneous beating via activation of GIRK channels. CONCLUSION AND IMPLICATIONS GA acts as a novel GIRK inhibitor, and 18β-GA acts as a novel GIRK activator. 18β-GA alters atrial function via activation of GIRK channels. This study elucidates the pharmacological activity of licorice ingredients and provides information for drug design.
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Affiliation(s)
- I-Shan Chen
- Department of Pharmacology, Faculty of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jumpei Yasuda
- Department of Pharmacology, Faculty of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takuya Notomi
- Department of Pharmacology, Faculty of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tomoe Y Nakamura
- Department of Pharmacology, Faculty of Medicine, Wakayama Medical University, Wakayama, Japan
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Del Calvo G, Pollard CM, Baggio Lopez T, Borges JI, Suster MS, Lymperopoulos A. Nicotine Diminishes Alpha2-Adrenergic Receptor-Dependent Protection Against Oxidative Stress in H9c2 Cardiomyocytes. Drug Des Devel Ther 2024; 18:71-80. [PMID: 38229917 PMCID: PMC10790636 DOI: 10.2147/dddt.s432453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 01/06/2024] [Indexed: 01/18/2024] Open
Abstract
INTRODUCTION Nicotine is a major component of cigarette smoke with various detrimental cardiovascular effects, including increased oxidative stress in the heart. Agonism of α2-adrenergic receptors (ARs), such as with dexmedetomidine, has been documented to exert cardioprotective effects against oxidative stress and related apoptosis and necroptosis. α2-ARs are membrane-residing G protein-coupled receptors (GPCRs) that primarily activate Gi/o proteins. They are also subjected to GPCR-kinase (GRK)-2-dependent desensitization, which entails phosphorylation of the agonist-activated receptor by GRK2 to induce its decoupling from G proteins, thus terminating α2AR-mediated G protein signaling. OBJECTIVE In the present study, we sought to examine the effects of nicotine on α2AR signaling and effects in H9c2 cardiomyocytes exposed to H2O2 to induce oxidative cellular damage. METHODS AND RESULTS As expected, treatment of H9c2 cardiomyocytes with H2O2 significantly decreased cell viability and increased oxidative stress, as assessed by reactive oxygen species (ROS)-associated fluorescence levels (DCF assay) and superoxide dismutase activity. Both H2O2 effects were partly rescued by α2AR activation with brimonidine in control cardiomyocytes but not in cells pretreated with nicotine for 24 hours, in which brimonidine was unable to reduce H2O2-induced cell death and oxidative stress. This was due to severe α2AR desensitization, manifested as very low Gi protein activation by brimonidine, and accompanied by GRK2 upregulation in nicotine-treated cardiomyocytes. Finally, pharmacological inhibition of adenylyl cyclase (AC) blocked H2O2-dependent oxidative damage in nicotine-pretreated H9c2 cardiomyocytes, indicating that α2AR activation protects against oxidative injury via its classic coupling to Gai-mediated AC inhibition. DISCUSSION/CONCLUSIONS Nicotine can negate the cardioprotective effects of α2AR agonists against oxidative injury, which may have important implications for patients treated with this class of drugs that are chronic tobacco smokers.
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Affiliation(s)
- Giselle Del Calvo
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
| | - Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
| | - Teresa Baggio Lopez
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
| | - Jordana I Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
| | - Malka S Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
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11
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Pu Y, Yang G, Pan X, Zhou Y, Zhong A, Ding N, Su Y, Peng W, Zeng M, Guo T, Chai X. Higher plasma aldosterone concentrations in patients with aortic diseases and hypertension: a retrospective observational study. Eur J Med Res 2023; 28:541. [PMID: 38008731 PMCID: PMC10676595 DOI: 10.1186/s40001-023-01528-2] [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: 03/07/2023] [Accepted: 11/14/2023] [Indexed: 11/28/2023] Open
Abstract
BACKGROUND Aortic diseases remain a highly perilous macrovascular condition. The relationship between circulating aldosterone and aortic diseases is rarely explored, thus we investigated the difference in plasma aldosterone concentration (PAC) between patients with and without aortic disease in hypertensive people. METHODS We analyzed 926 patients with hypertension, ranging in age from 18 to 89 years, who had their PAC measured from the hospital's electronic database. The case group and control group were defined based on inclusion and exclusion criteria. The analysis included general information, clinical data, biochemical data, and medical imaging examination results as covariates. To further evaluate the difference in PAC between primary hypertension patients with aortic disease and those without, we used multivariate logistic regression analysis and also employed propensity score matching to minimize the influence of confounding factors. RESULTS In total, 394 participants were included in the analysis, with 66 individuals diagnosed with aortic diseases and 328 in the control group. The participants were predominantly male (64.5%) and over the age of 50 (68.5%), with an average PAC of 19.95 ng/dL. After controlling for confounding factors, the results showed hypertension patients with aortic disease were more likely to have high PAC levels than those without aortic disease (OR = 1.138, 95% CI [1.062 to 1.238]). Subgroup analysis revealed consistent relationship between PAC and primary hypertensive patients with aortic disease across the different stratification variables. Additionally, hypertensive patients with aortic disease still have a risk of higher PAC levels than those without aortic disease, even after propensity score matching. CONCLUSIONS The results of this study suggest that primary hypertensive patients with aortic diseases have elevated levels of PAC, but the causal relationship between PAC and aortic disease requires further study.
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Affiliation(s)
- Yuting Pu
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guifang Yang
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaogao Pan
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Zhou
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Aifang Zhong
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ning Ding
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yingjie Su
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wen Peng
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengping Zeng
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tuo Guo
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiangping Chai
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.
- Emergency Medicine and Difficult Disease Institute, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
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12
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Li X, Kuang W, Qiu Z, Zhou Z. G protein-coupled estrogen receptor: a promising therapeutic target for aldosterone-induced hypertension. Front Endocrinol (Lausanne) 2023; 14:1226458. [PMID: 37664844 PMCID: PMC10471144 DOI: 10.3389/fendo.2023.1226458] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/18/2023] [Indexed: 09/05/2023] Open
Abstract
Aldosterone is one of the most essential hormones synthesized by the adrenal gland because it regulates water and electrolyte balance. G protein-coupled estrogen receptor (GPER) is a newly discovered aldosterone receptor, which is proposed to mediate the non-genomic pathways of aldosterone while the hormone simultaneously interacts with mineralocorticoid receptor. In contrast to its cardio-protective role in postmenopausal women via its interaction with estrogen, GPER seems to trigger vasoconstriction effects and can further induce water and sodium retention in the presence of aldosterone, indicating two entirely different binding sites and effects for estrogen and aldosterone. Accumulating evidence also points to a role of aldosterone in mediating hypertension and its risk factors via the interaction with GPER. Therefore, with this review, we aimed to summarize the research on these interactions to help (1) elucidate the role of GPER activated by aldosterone in the blood vessels, heart, and kidney; (2) compare the non-genomic actions between aldosterone and estrogen mediated by GPER; and (3) address the potential of GPER as a new promising therapeutic target for aldosterone-induced hypertension.
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Affiliation(s)
- Xuehan Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenlong Kuang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihua Qiu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihua Zhou
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Kmieć P, Rosenkranz S, Odenthal M, Caglayan E. Differential Role of Aldosterone and Transforming Growth Factor Beta-1 in Cardiac Remodeling. Int J Mol Sci 2023; 24:12237. [PMID: 37569619 PMCID: PMC10419155 DOI: 10.3390/ijms241512237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-β1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-β1-overexpressing transgenic (TGF-β1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts' ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-β1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-β1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-β1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.
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Affiliation(s)
- Piotr Kmieć
- Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, 80214 Gdańsk, Poland;
| | - Stephan Rosenkranz
- Clinic for Internal Medicine III and Cologne Cardiovascular Research Center, Cologne University Heart Center, 50937 Köln, Germany;
| | - Margarete Odenthal
- Institute of Pathology, University Hospital of Cologne and Center for Molecular Medicine, University of Cologne, 50937 Köln, Germany;
| | - Evren Caglayan
- Department of Cardiology, University-Medicine Rostock, 18057 Rostock, Germany
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14
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Parksook WW, Williams GH. Aldosterone and cardiovascular diseases. Cardiovasc Res 2023; 119:28-44. [PMID: 35388416 DOI: 10.1093/cvr/cvac027] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/07/2021] [Accepted: 12/28/2021] [Indexed: 11/12/2022] Open
Abstract
Aldosterone's role in the kidney and its pathophysiologic actions in hypertension are well known. However, its role or that of its receptor [minieralocorticoid receptor (MR)] in other cardiovascular (CV) disease are less well described. To identify their potential roles in six CV conditions (heart failure, myocardial infarction, atrial fibrillation, stroke, atherosclerosis, and thrombosis), we assessed these associations in the following four areas: (i) mechanistic studies in rodents and humans; (ii) pre-clinical studies of MR antagonists; (iii) clinical trials of MR antagonists; and (iv) genetics. The data were acquired from an online search of the National Library of Medicine using the PubMed search engine from January 2011 through June 2021. There were 3702 publications identified with 200 publications meeting our inclusion and exclusion criteria. Data strongly supported an association between heart failure and dysregulated aldosterone/MR. This association is not surprising given aldosterone/MR's prominent role in regulating sodium/volume homeostasis. Atrial fibrillation and myocardial infarction are also associated with dysregulated aldosterone/MR, but less strongly. For the most part, the data were insufficient to determine whether there was a relationship between atherosclerosis, stroke, or thrombosis and aldosterone/MR dysregulation. This review clearly documented an expanding role for aldosterone/MR's dysregulation in CV diseases beyond hypertension. How expansive it might be is limited by the currently available data. It is anticipated that with an increased focus on aldosterone/MR's potential roles in these diseases, additional clinical and pre-clinical data will clarify these relationships, thereby, opening approaches to use modulators of aldosterone/MR's action to more precisely treat these CV conditions.
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Affiliation(s)
- Wasita W Parksook
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Division of Endocrinology and Metabolism, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Division of General Internal Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Gordon H Williams
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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15
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Nagasaka A, Terawaki T, Noda M, Takashima M, Fujino M, Yamauchi Y, Arawaka S, Kato T, Nakaya M. GRK5-mediated inflammation and fibrosis exert cardioprotective effects during the acute phase of myocardial infarction. FEBS Open Bio 2023; 13:380-391. [PMID: 36633120 PMCID: PMC9900089 DOI: 10.1002/2211-5463.13551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 11/19/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023] Open
Abstract
During myocardial infarction (MI), cardiac cells at the infarcted area undergo cell death. In response, cardiac myofibroblasts, which are mainly differentiated from resident fibroblasts upon inflammation, produce extracellular matrix proteins such as collagen to fill the damaged areas of the heart to prevent cardiac rupture. In this study, we identified a cardioprotective role of G-protein-coupled receptor kinase 5 (GRK5) in MI. GRK5 expression was found to increase in the mouse heart after MI and was highly expressed in cardiac fibroblasts/myofibroblasts. In fibroblasts/myofibroblasts, GRK5 promoted the expression of inflammation-related genes through nuclear factor-κB activation, leading to an increase in the expression levels of fibrosis-related genes. Bone marrow transfer experiments confirmed that GRK5 in fibroblasts/myofibroblasts, but not in infiltrated macrophages in the infarcted area, is mainly responsible for GRK5-mediated inflammation in infarcted hearts. In addition, inflammation and fibrosis at the infarcted area were significantly suppressed in GRK5 knockout mice, resulting in increased mortality compared with that in wild-type mice. These data indicate that GRK5 in cardiac fibroblasts/myofibroblasts promotes inflammation and fibrosis to ameliorate the damage after MI.
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Affiliation(s)
- Akiomi Nagasaka
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Tsuyoshi Terawaki
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Makoto Noda
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Miyuki Takashima
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Mika Fujino
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Yuto Yamauchi
- Department of Disease control, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
| | - Shigeki Arawaka
- Division of Neurology, Department of Internal Medicine IVOsaka Medical CollegeJapan
| | - Takeo Kato
- Division of Neurology and Clinical Neuroscience, Department of Internal Medicine IIIYamagata University School of MedicineJapan
| | - Michio Nakaya
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
- Department of Disease control, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
- AMED‐PRIMEJapan Agency for Medical Research and DevelopmentTokyoJapan
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16
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Carbone AM, Borges JI, Suster MS, Sizova A, Cora N, Desimine VL, Lymperopoulos A. Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling. Int J Mol Sci 2022; 23:5803. [PMID: 35628613 PMCID: PMC9147283 DOI: 10.3390/ijms23105803] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/16/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open
Abstract
Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate's actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.
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Affiliation(s)
| | | | | | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA; (A.M.C.); (J.I.B.); (M.S.S.); (A.S.); (N.C.); (V.L.D.)
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17
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Pollard CM, Suster MS, Cora N, Carbone AM, Lymperopoulos A. GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone. World J Cardiol 2022; 14:220-230. [PMID: 35582468 PMCID: PMC9048278 DOI: 10.4330/wjc.v14.i4.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/17/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. METHODS We used H9c2 cardiomyocytes, which endogenously express the MR and GRK5. RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone's inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally, GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis, oxidative stress, and fibrosis. CONCLUSION Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.
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Affiliation(s)
- Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Malka S Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States.
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Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate. Int J Mol Sci 2022; 23:ijms23074009. [PMID: 35409368 PMCID: PMC8999971 DOI: 10.3390/ijms23074009] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 12/30/2022] Open
Abstract
The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.
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Mineralocorticoid receptor actions in cardiovascular development and disease. Essays Biochem 2021; 65:901-911. [PMID: 34414409 DOI: 10.1042/ebc20210006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/31/2022]
Abstract
Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol. The pathology of inappropriate MR activation in non-epithelial tissues are well-described, and steroidal antagonists of the MR have been clinically beneficial in the management of heart failure and blood pressure for decades. However, the role of cortisol-dependent MR activation in the physiological setting is less well defined. Like other steroid hormone receptors, the MR also regulates non-DNA-binding pathways including MAPK pathways and G protein coupled receptors to provide diversity to MR signaling. Whether nonDNA binding pathways are more relevant for MR activation in non-epithelial, versus epithelial, tissues remain unclear. This review will focus on molecular regulation of ligand-dependent MR activation and the physiology and pathophysiology of MR actions in the heart with a focus on the cardiomyocyte and provide a discussion of relevant genomic and non-genomic MR pathways and potential new transcriptional partners for the MR and their relevance for health and disease. Understanding MR actions in the heart will provide new insights into cell-selective mechanisms that underpin the therapeutic benefits of MRAs, and are a critical step towards developing next-generation tissue selective MR modulators with improved safety profiles.
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Maning J, McCrink KA, Pollard CM, Desimine VL, Ghandour J, Perez A, Cora N, Ferraino KE, Parker BM, Brill AR, Aukszi B, Lymperopoulos A. Correction: Maning et al. Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. Int. J. Mol. Sci. 2020, 21, 2868. Int J Mol Sci 2021; 22:7767. [PMID: 34361122 PMCID: PMC8346130 DOI: 10.3390/ijms22157767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/15/2021] [Indexed: 11/24/2022] Open
Abstract
The authors wish to make the following correction to this paper [...].
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Affiliation(s)
- Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Katie A. McCrink
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Celina M. Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Victoria L. Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Jennifer Ghandour
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Arianna Perez
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Krysten E. Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Barbara M. Parker
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Ava R. Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Beatrix Aukszi
- Department of Chemistry and Physics, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
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Guitart-Mampel M, Urquiza P, Borges JI, Lymperopoulos A, Solesio ME. Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function. Cells 2021; 10:1552. [PMID: 34205363 PMCID: PMC8235589 DOI: 10.3390/cells10061552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)-particularly βARs-play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.
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Affiliation(s)
- Mariona Guitart-Mampel
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Pedro Urquiza
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Jordana I. Borges
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Maria E. Solesio
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
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Gadasheva Y, Nolze A, Grossmann C. Posttranslational Modifications of the Mineralocorticoid Receptor and Cardiovascular Aging. Front Mol Biosci 2021; 8:667990. [PMID: 34124152 PMCID: PMC8193679 DOI: 10.3389/fmolb.2021.667990] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/07/2021] [Indexed: 01/05/2023] Open
Abstract
During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases.
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Affiliation(s)
- Yekatarina Gadasheva
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Alexander Nolze
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Claudia Grossmann
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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Coleman RC, Eguchi A, Lieu M, Roy R, Barr EW, Ibetti J, Lucchese AM, Peluzzo AM, Gresham K, Chuprun JK, Koch WJ. A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure. Sci Signal 2021; 14:14/676/eabb5968. [PMID: 33785612 DOI: 10.1126/scisignal.abb5968] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein-coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that binds to calmodulin (CaM). Here, we sought to prevent GRK5-mediated pathology in pressure-overload maladaptation and heart failure by expressing in cardiomyocytes a peptide encoding the GRK5 NT (GRK5nt) that encompasses the CaM binding domain. In cultured cardiomyocytes, GRK5nt expression abrogated Gq-coupled receptor-mediated hypertrophy, including attenuation of pathological gene expression and the transcriptional activity of NFAT and NF-κB. We confirmed that GRK5nt bound to and blocked Ca2+-CaM from associating with endogenous GRK5, thereby preventing GRK5 nuclear accumulation after pressure overload. We generated mice that expressed GRKnt in a cardiac-specific fashion (TgGRK5nt mice), which exhibited reduced cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis after chronic transverse aortic constriction. Together, our data support a role for GRK5nt as an inhibitor of pathological GRK5 signaling that prevents heart failure.
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Affiliation(s)
- Ryan C Coleman
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Akito Eguchi
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Melissa Lieu
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Rajika Roy
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Eric W Barr
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Jessica Ibetti
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Anna-Maria Lucchese
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Amanda M Peluzzo
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Kenneth Gresham
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - J Kurt Chuprun
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Walter J Koch
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
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Arcones AC, Martínez-Cignoni MR, Vila-Bedmar R, Yáñez C, Lladó I, Proenza AM, Mayor F, Murga C. Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones. Cells 2021; 10:673. [PMID: 33803070 PMCID: PMC8002941 DOI: 10.3390/cells10030673] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/23/2022] Open
Abstract
Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.
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Affiliation(s)
- Alba C. Arcones
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, Universidad Autónoma Madrid, 28049 Madrid, Spain; (A.C.A.); (R.V.-B.); (C.Y.); (F.M.J.)
- Instituto de Investigación Sanitaria Hospital Universitario La Princesa and CIBER Cardiovascular (CIBERCV), ISCIII, 28028 Madrid, Spain
| | - Melanie Raquel Martínez-Cignoni
- Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07122 Palma, Spain; (M.R.M.-C.); (I.L.); (A.M.P.)
| | - Rocío Vila-Bedmar
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, Universidad Autónoma Madrid, 28049 Madrid, Spain; (A.C.A.); (R.V.-B.); (C.Y.); (F.M.J.)
- Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Biología Molecular, URJC, 28922 Madrid, Spain
| | - Claudia Yáñez
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, Universidad Autónoma Madrid, 28049 Madrid, Spain; (A.C.A.); (R.V.-B.); (C.Y.); (F.M.J.)
| | - Isabel Lladó
- Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07122 Palma, Spain; (M.R.M.-C.); (I.L.); (A.M.P.)
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Ana M. Proenza
- Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07122 Palma, Spain; (M.R.M.-C.); (I.L.); (A.M.P.)
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Federico Mayor
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, Universidad Autónoma Madrid, 28049 Madrid, Spain; (A.C.A.); (R.V.-B.); (C.Y.); (F.M.J.)
- Instituto de Investigación Sanitaria Hospital Universitario La Princesa and CIBER Cardiovascular (CIBERCV), ISCIII, 28028 Madrid, Spain
| | - Cristina Murga
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, Universidad Autónoma Madrid, 28049 Madrid, Spain; (A.C.A.); (R.V.-B.); (C.Y.); (F.M.J.)
- Instituto de Investigación Sanitaria Hospital Universitario La Princesa and CIBER Cardiovascular (CIBERCV), ISCIII, 28028 Madrid, Spain
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Targeting GRK5 for Treating Chronic Degenerative Diseases. Int J Mol Sci 2021; 22:ijms22041920. [PMID: 33671974 PMCID: PMC7919044 DOI: 10.3390/ijms22041920] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/27/2022] Open
Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated by a family of serine/threonine kinases, called GPCR kinases (GRKs). Given the biological role of GPCRs, it is not surprising that GRKs are also involved in several pathophysiological processes. Particular importance is emerging for GRK5, which is a multifunctional protein, expressed in different cell types, and it has been found located in single or multiple subcellular compartments. For instance, when anchored to the plasma membrane, GRK5 exerts its canonical function, regulating GPCRs. However, under certain conditions (e.g., pro-hypertrophic stimuli), GRK5 translocates to the nucleus of cells where it can interact with non-GPCR-related proteins as well as DNA itself to promote “non-canonical” signaling, including gene transcription. Importantly, due to these actions, several studies have demonstrated that GRK5 has a pivotal role in the pathogenesis of chronic-degenerative disorders. This is true in the cardiac cells, tumor cells, and neurons. For this reason, in this review article, we will inform the readers of the most recent evidence that supports the importance of targeting GRK5 to prevent the development or progression of cancer, cardiovascular, and neurological diseases.
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