TY - JOUR
T1 - Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure
AU - Gesmundo, Iacopo
AU - Miragoli, Michele
AU - Carullo, Pierluigi
AU - Trovato, Letizia
AU - Larcher, Veronica
AU - Di Pasquale, Elisa
AU - Brancaccio, Mara
AU - Mazzola, Marta
AU - Villanova, Tania
AU - Sorge, Matteo
AU - Taliano, Marina
AU - Gallo, Maria Pia
AU - Alloatti, Giuseppe
AU - Penna, Claudia
AU - Hare, Joshua M.
AU - Ghigo, Ezio
AU - Schally, Andrew V.
AU - Condorelli, Gianluigi
AU - Granata, Riccarda
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the Neuroscience Institute of Turin. This work was supported by a European Research Council Advanced Grant (CardioEpigen, 294609), the Italian Ministry of Health (PE-2013-02356818), PRIN (Italian Ministry of Research and Education) 2015583WMX, and Fondazione CARIPLO Grant 2015-0573 (all to G.C.); PRIN 2010-B5B2NL (to E.G.); Fondazione CRT 2015/273 and University of Turin Ex-60% 2014 and 2015 (to R.G.); and NIH Grants R01 HL107110, R01 HL084275, UM1 HL113460, and R01 HL110737 (to J.M.H.). The work in the laboratory of A.V.S. was supported by the Medical Research Service of the Veterans Affairs Department and University of Miami Miller School of Medicine.
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/11/7
Y1 - 2017/11/7
N2 - 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 Ce, 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.
AB - 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 Ce, 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.
KW - Cardiac hypertrophy
KW - Growth hormone-releasing hormone
KW - Heart failure
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U2 - 10.1073/pnas.1712612114
DO - 10.1073/pnas.1712612114
M3 - Article
C2 - 29078377
AN - SCOPUS:85033463011
VL - 114
SP - 12033
EP - 12038
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 45
ER -