Cardiomyocyte-specific expression of HIF-1α mediates the cardioprotective effects of growth hormone-releasing hormone.

Heart failure (HF) with preserved ejection fraction (HFpEF) carries a high mortality and remains a major therapeutic challenge. Effective targeted therapies capable of reversing HFpEF pathophysiology are urgently needed. We previously demonstrated that activation of the cardiac growth hormone-releasing hormone (GHRH) pathway using high potency synthetic agonists of GHRH (GHRH-agonists) improves the HFpEF phenotype in both large and small animal models, including in a murine model of cardiometabolic HFpEF [high-fat diet + Nω-nitro-l-arginine methyl ester (l-NAME)]. Here we sought to define the downstream signaling pathways responsible for this effect. A transcriptomic screen in human inducible-pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CMs) identified the hypoxia-induced factor (HIF-1α) pathway as being activated by GHRH receptor (GHRHR) signaling, revealing an oxygen-independent mechanism of HIF-1α activation. Based on this finding, we investigated the interaction between the cardioprotective effects of the GHRH-agonist MR-356 and HIF-1α pathway activation in the murine HFD + l-NAME model of cardiometabolic HFpEF. We generated a cardiomyocyte-specific HIF-1α knockout (HIF-1αCMKO) mouse line and demonstrated that our previously reported beneficial effects of GHRH-agonist administration were completely abolished in HIF-1αCMKO mice. Together, these findings establish the GHRHR-HIF-1α axis as a putative integrative pathway coupling metabolic and contractile remodeling, suggesting that therapeutic targeting of this axis represents a novel disease-modifying approach to treating cardiometabolic HFpEF.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) lacks effective disease-modifying therapies. This study identifies a novel cardioprotective mechanism in which growth hormone-releasing hormone activates hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes under normoxic conditions. Using human iPSC-derived cardiomyocytes and a cardiometabolic HFpEF mouse model, the authors show that cardiomyocyte HIF-1α is required for GHRH-mediated improvements in diastolic function, myocardial mechanics, and exercise capacity, revealing a previously unrecognized therapeutic axis for HFpEF.