Epigenetic Regulation of Heart Failure with Preserved Ejection Fraction - PROJECT SUMMARY/ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects ~3 million Americans and is driven by obesity and hypertension. HFpEF is characterized by diastolic dysfunction of the heart, lung edema, impaired skeletal muscle work, elevated circulating liver enzymes, and fluid retention by the kidneys. As a systemic disease, new treatments for HFpEF are likely to arise from investigations across multiple organs. Indeed, emergent HFpEF therapies in humans, including SGLT2 inhibition and GLP1 agonism, both independently have effects on multiple organ systems including decreasing appetite, glucose levels, and body weight, in addition to improving cardiac HFpEF phenotypes like ventricular stiffening and diastolic function. In unpublished data for this proposal, we have shown these therapies to be effective in the ZSF1 rat, providing strong premise to use this model system to develop a greater basic and translational understanding of HFpEF. While previous work has implicated chromatin alterations in other forms of heart disease, epigenomic and transcriptomic reprogramming in HFpEF is not understood. We hypothesize that chromatin remodeling and transcriptome regulatory pathways are mobilized across different organs in response to metabolic and hemodynamic stress, setting into motion the pathologic phenotypes of HFpEF. Our goal is to reveal the molecular insights into the actions of widely used drugs such as empagliflozin (SGLT2 inhibitor) and semaglutide (GLP1 agonist) across multiple organs and to identify novel therapeutic targets in HFpEF. We will measure transcription, chromatin accessibility and histone modifications in heart, kidney and liver, to map the regulatory landscape during the development of HFpEF in a well-established rat model. These studies will provide the first detailed, multi-organ epigenomic atlases of HFpEF, while simultaneously biobanking adipose, blood, aorta and skeletal muscle for future analyses. This proposal will also enable identification of transcription factors and chromatin remodelers operative in heart, liver or kidney, to determine the temporal and causal relationships of multi-organ dysfunction in HFpEF. We will leverage PharmOmics to interrogate these networks for the purposes of re-positioning existing drugs and prioritizing molecular targets. Finally, we will test a newly identified molecular target, histone H1.0, which we have recently shown is necessary for fibroblast activation and fibrosis in vivo. We will modulate histone H1.0 levels in the ZSF1 rat model using AAV9, with readouts including cardiac, lung, liver, kidney physiology and exercise capacity. We hypothesize that greater levels of histone H1.0 promote fibrosis and tissue stiffening—exacerbating the phenotypes of HFpEF—and that targeted depletion of histone H1.0 can counteract these effects. This proposal will provide the first heart, liver and kidney analyses of the epigenomic and transcriptomic underpinning of HFpEF pathogenesis, examining the molecular basis for the beneficially effects of emergent HFpEF therapies across organ systems.
