Abstract Body: Introduction: HFpEF features diastolic dysfunction with metabolic inflexibility and fibrosis, yet gene-level changes can be subtle. We previously showed that activating the cardiac growth hormone-releasing hormone (GHRH) pathway with the synthetic agonist MR356 reverses or attenuates HFpEF features. Our preliminary results reveal that GHRH-receptor signaling activates the PI3K/Akt/ mTOR/HIF1α pathway in a hypoxia-independent manner. Hypothesis: Cardiomyocyte-specific expression of HIF-1α is required for the therapeutic actions of a GHRH-agonist (MR356).
Methods: Male and female cardiomyocyte-specific HIF1α knockout (HIF1α^CMKO) and wild-type (WT) mice were studied in a murine HFpEF model. Blood pressure, glucose, echocardiography (including IVRT, E/E′, GLS), and exercise exhaustion were assessed at 5 and 9 weeks; terminal hemodynamics and gravimetry were recorded. Bulk RNA-seq interrogated transcriptomic changes.
Results: WT, and HIF1α^CMKO developed comparable HFpEF phenotype. MR356 did not lower blood pressure or glucose in either genotype but restored diastolic function (normalization of IVRT and E/E′) and improved GLS and exercise capacity only in WT. Overall, gene-level RNA seq differences were modest, but pathway enrichment analysis revealed coordinated downregulation of mitochondrial bioenergetics, including oxidative phosphorylation, electron transport (Complex I), proton motive force ATP synthesis, with additional perturbations in mitochondrial translation/gene expression in HIF1α^CMKO animals. No upregulated pathways passed significance, with nominal trends in ECM/collagen, GPCR inflammatory, and cilium/axon guidance programs. These pathway level shifts indicate targeted, biologically coherent remodeling align with the observed diastolic/functional rescue in WT.
Conclusions: Consistent with our previous findings, MR356 reverses most key features of HFpEF, and these benefits require cardiomyocyte-specific expression of HIF1α. The transcriptomic signature provides a mechanistic basis for genotype-dependent efficacy and indicates HIF1α-linked mitochondrial and translational pathways as biomarkers and targets for precision HFpEF therapy.