Synthetic growth hormone-releasing hormone agonist ameliorates the myocardial pathophysiology characteristic of heart failure with preserved ejection fraction.

Autor:	Dulce RA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA., Kanashiro-Takeuchi RM; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA.; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Takeuchi LM; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA., Salerno AG; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA., Wanschel ACBA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA., Kulandavelu S; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA.; Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Balkan W; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA.; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Zuttion MSSR; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA., Cai R; Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, FL 33125, USA., Schally AV; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, FL 33125, USA.; Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Hare JM; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 N.W. 10th Avenue, Room 908, Miami, FL 33136, USA.; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Feb 03; Vol. 118 (18), pp. 3586-3601.
DOI:	10.1093/cvr/cvac098
Abstrakt:	Aims: To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis. Methods and Results: CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts. Conclusion: These findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome. Competing Interests: Conflict of interest: A.V.S. and J.M.H. are listed as co-inventors on patents on GHRH analogues which were assigned to the University of Miami and Veterans Affairs Department. J.M.H. previously owned equity in Biscayne Pharmaceuticals, license of intellectual property used in this study. Biscayne Pharmaceuticals did not provide funding for this study. J.M.H. reported having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. J.M.H. is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron, and holds equity in Longeveron. He is also the co-inventor of intellectual property licensed to Longeveron. Longeveron LLC and Vestion Inc. did not participate in funding this work. J.M.H.’s relationships are disclosed to the University of Miami, and a management plan is in place. All other authors have declared that no conflict of interest exists. (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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