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

Iacopo Gesmundo, Michele Miragoli, Pierluigi Carullo, Letizia Trovato, Veronica Larcher, Elisa Di Pasquale, Mara Brancaccio, Marta Mazzola, Tania Villanova, Matteo Sorge, Marina Taliano, Maria Pia Gallo, Giuseppe Alloatti, Claudia Penna, Joshua Hare, Ezio Ghigo, Andrew V Schally, Gianluigi Condorelli, Riccarda Granata

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12033-12038
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number45
DOIs
StatePublished - Nov 7 2017

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Growth Hormone-Releasing Hormone
Cardiomegaly
Heart Failure
Pressure
Constriction
Induced Pluripotent Stem Cells
Calcineurin
Type C Phospholipases
Phenylephrine
Reperfusion Injury
Cardiac Myocytes
Protein Kinases
Muscle Cells
Hypertrophy
Apoptosis
Gene Expression
Therapeutics

Keywords

  • Cardiac hypertrophy
  • Growth hormone-releasing hormone
  • Heart failure

ASJC Scopus subject areas

  • General

Cite this

Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure. / 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; Ghigo, Ezio; Schally, Andrew V; Condorelli, Gianluigi; Granata, Riccarda.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 45, 07.11.2017, p. 12033-12038.

Research output: Contribution to journalArticle

Gesmundo, I, Miragoli, M, Carullo, P, Trovato, L, Larcher, V, Di Pasquale, E, Brancaccio, M, Mazzola, M, Villanova, T, Sorge, M, Taliano, M, Gallo, MP, Alloatti, G, Penna, C, Hare, J, Ghigo, E, Schally, AV, Condorelli, G & Granata, R 2017, 'Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 45, pp. 12033-12038. https://doi.org/10.1073/pnas.1712612114
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 ; Ghigo, Ezio ; Schally, Andrew V ; Condorelli, Gianluigi ; Granata, Riccarda. / Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 45. pp. 12033-12038.
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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

AU - Ghigo, Ezio

AU - Schally, Andrew V

AU - Condorelli, Gianluigi

AU - Granata, Riccarda

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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.

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