Abstract P2085: Growth Hormone Releasing Hormone Agonist Counteracts The Cardiometabolic Heart Failure With Preserved Ejection Fraction Phenotype In Vivo Via The Hypoxia Inducible Factor 1 Alpha

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) treatment is limited due in large part to a lack of understanding of the underlying mechanisms. Recently, we showed that growth hormone-releasing hormone-agonist (GHRH-agonist) has cardioprotective effects in a murine model of cardiometabolic HFpEF; however, the mechanism of these therapeutic effects is still unclear. Here, we hypothesize that the therapeutic effects of GHRH-agonist in HFpEF are mediated by GHRH-receptor activation of the hypoxia-induced factor (HIF)-1α pathway. Methods: Wild-type (WT) and HIF-1α cardiomyocyte knockout (HIF-1α CM KO) mice were fed 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 received daily injections of placebo or the GHRH-agonist, MR-356, for the remaining 4-week period. Control animals received no HFD+L-NAME or MR-356 treatment. Echocardiography, blood pressure, glucose tolerance test, and hemodynamic measurements were evaluated. Results: The HFD+L-NAME diet produced a HFpEF phenotype, which was reversed in mice with intact HIF-1α treated with MR-356. In contrast, in mice with a cardiac-specific deletion of HIF-1α CM , MR-356 treatment failed to reverse the elevated relative wall thickness in diastole (RWTd), increased E/E’ ratio and reduced global longitudinal strain (GLS). The slope of end-diastolic pressure-volume relationship (EDPVR) was increased in the placebo group and restored by MR-356 in WT mice but not HIF-1α CM KO mice, while EF was preserved. Conclusion: Our findings suggest that HIF-1α is necessary for the cardioprotective and anti-HFpEF effects MR-356.