Synthetic Agonist of Growth Hormone-Releasing Hormone as Novel Treatment for Heart Failure with Preserved Ejection Fraction

Abstract

ObjectiveTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses heart failure with preserved ejection fraction (HFpEF). BackgroundHFpEF is characterized by impaired myocardial relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, hypertrophy and improve performance, independently of the growth-hormone axis. MethodsWe generated a HFpEF-like phenotype with continuous infusion of angiotensin-II (Ang-II) in CD1 mice. Mice were injected with either vehicle or a potent synthetic agonist of the growth hormone-releasing hormone, MR-356. ResultsAng-II treated animals had diastolic dysfunction, ventricular hypertrophy, and normal ejection fraction and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. ConclusionThese findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocyte dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of the HFpEF syndrome. Condensed abstractHeart failure with preserved ejection fraction (HFpEF) is characterized by a remodeled myocardium conferring ventricular stiffness and diastolic dysfunction. There are no effective therapies. Agonists of growth hormone-releasing hormone (GHRH) receptors have beneficial effects on the heart. We hypothesize that activation of GHRH receptors suppresses this HFpEF phenotype. Treatment with a synthetic agonist of GHRH, prevented the development of the pathological phenotype in a murine model of HFpEF-induced by chronic angiotensin-II infusion. These findings indicate that activation of GHRH receptors represents a novel molecular strategy to counteract HFpEF-associated cardiomyocyte dysfunction and provide a potential approach to management of HFpEF syndrome. HighlightsO_LIA synthetic growth hormone-releasing hormone agonist (GHRH-A) prevents and reverses the pathological remodeling in a mouse model of HFpEF induced by infusion of low dose Ang II. C_LIO_LIGHRH-A improves intracellular calcium handling by reducing the sarcoplasmic reticulum calcium leakage and enhancing phospholamban phosphorylation. C_LIO_LIGHRH-A treatment prevents and reverses diastolic dysfunction by enhancing the rate of sarcomere re-lengthening. C_LIO_LIActivation of the GHRH receptor with the GHRH-A, MR-356, leads to targeting myofibrillar proteins and desensitizing myofilaments in response to calcium. C_LI