Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 45; pp. 12033 - 12038
• Main Authors: Gesmundo, Iacopo, Miragoli, Michele, Carullo, Pierluigi, Trovato, Letizia, Larcher, Veronica, Di Pasquale, Elisa, Brancaccio, Mara, Mazzola, Marta, Villanova, Tania, Sorge, Matteo, Taliano, Marina, Gallo, Maria Pia, Alloatti, Giuseppe, Penna, Claudia, Hare, Joshua M., Ghigo, Ezio, Schally, Andrew V., Condorelli, Gianluigi, Granata, Riccarda
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.11.2017
• Subjects: Animals; Aorta; Apoptosis; Apoptosis - drug effects; Beneficial use; Biological Sciences; Calcineurin; Calcineurin - metabolism; Cardiac muscle; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomyocytes; Cell Line; Cyclic AMP-Dependent Protein Kinases - metabolism; Eutrophication; Gene expression; Growth hormone; Growth hormone-releasing hormone; Growth Hormone-Releasing Hormone - metabolism; Growth hormones; Heart - physiology; Heart diseases; Heart failure; Heart Failure - metabolism; Heart function; Humans; Hypertrophy; Injury prevention; Ischemia; Male; Mice; Mice, Inbred C57BL; Muscle contraction; Myocardium - metabolism; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Phenylephrine; Phenylephrine - pharmacology; Phospholamban; Phospholipase; Phospholipase C; Phospholipase C beta - metabolism; Pluripotency; Pressure; Protein kinase A; Protein kinase C; Protein Kinase C - metabolism; Rats; Reperfusion; Rodents; Signal Transduction - drug effects; Signaling; Stem cells; Ventricle; cardiac hypertrophy; heart failure; growth hormone-releasing hormone
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1712612114

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH₂ attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.