AJP - Supplemental Data - Kanashiro-Takeuchi- Cardiomyocyte-Specific Expression of HIF-1a Mediates the Cardioprotective Effects of Growth Hormone-Releasing Hormone (GHRH)

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 + L-NAME). Here, we sought to define the downstream signaling pathways responsible for this effect. A transcriptomic screen in human iPSC-derived cardiomyocytes (hiPSC-CMs) identified the HIF-1a pathway as being activated by GHRH receptor (GHRHR) signaling, revealing an oxygen-independent mechanism of HIF-1a activation. Based on this finding, we investigated the interaction between the cardioprotective effects of the GHRH-agonist MR-356 and HIF-1a pathway activation in the murine HFD+L-NAME model of cardiometabolic HFpEF. We generated a cardiomyocyte-specific HIF-1a knockout (HIF-1aCMKO) mouse line and demonstrated that our previously reported beneficial effects of GHRH-agonist administration were completely abolished in HIF-1aCMKO mice. Together, these findings establish the GHRHR-HIF-1a axis as a central pathway integrating metabolic and contractile remodeling, suggesting that therapeutic targeting of this axis represents a novel disease-modifying approach to treating cardiometabolic HFpEF.