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Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure
Iacopo Gesmundo1, Michele Miragoli2,3,4, Pierluigi Carullo2,4
1Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Insights
Growth hormone-releasing hormone (GHRH) can treat cardiac hypertrophy and heart failure. GHRH analogs like MR-409 show therapeutic potential by improving cardiac function and reversing cellular damage in preclinical models.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Growth hormone-releasing hormone (GHRH) is known to protect the heart from injury.
- Its therapeutic potential in pathological cardiac hypertrophy and heart failure (HF) remains unexplored.
Purpose of the Study:
- To investigate the efficacy of GHRH and its analog MR-409 in treating cardiac hypertrophy and heart failure.
- To elucidate the underlying molecular mechanisms of GHRH's cardioprotective effects.
Main Methods:
- In vitro studies using cell lines (H9c2, iPSC-CMs) and adult rat ventricular myocytes exposed to phenylephrine.
- In vivo studies involving transverse aortic constriction (TAC) in mice treated with MR-409.
- Analysis of hypertrophic gene expression, signaling pathways (Gq, Gαs, cAMP/PKA, Epac1), and cardiomyocyte contractility.
Main Results:
- GHRH attenuated phenylephrine-induced cardiac hypertrophy in vitro by blocking Gq signaling and modulating cAMP/PKA pathways.
- MR-409 treatment mitigated cardiac hypertrophy and improved cardiac function in TAC mice.
- Isolated cardiomyocytes from treated mice exhibited enhanced contractility and structural improvements.
Conclusions:
- GHRH acts as an antihypertrophic regulator, demonstrating significant therapeutic potential for heart failure.
- GHRH analogs like MR-409 may offer a novel treatment strategy for pathological cardiac hypertrophy.
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 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.