TY - JOUR T1 - Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction JF - bioRxiv DO - 10.1101/2022.09.18.508429 SP - 2022.09.18.508429 AU - Rosemeire M. Kanashiro-Takeuchi AU - Lauro M. Takeuchi AU - Raul A. Dulce AU - Katarzyna Kazmierczak AU - Wayne Balkan AU - Renzhi Cai AU - Wei Sha AU - Andrew V. Schally AU - Joshua M. Hare Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/09/19/2022.09.18.508429.abstract N2 - Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system, aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-week period. Control animals received no HFD+L-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.Competing Interest StatementDr. Joshua Hare owned equity in Biscayne Pharmaceuticals, licensee of intellectual property used in this study. Biscayne Pharmaceuticals did not provide funding for this study. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron and holds equity in Longeveron. Dr. Hare is also the co-inventor of intellectual property licensed to Longeveron. All other authors have declared that no conflict of interest exists. ER -