Heart failure with preserved ejection fraction (HFpEF), characterized by multiple cardiometabolic abnormalities, represents a major and growing health burden with limited treatment options. Although pan-histone deacetylase inhibitors (HDACi) improve diastolic function in preclinical models, their side effects emphasize the need for selective HDAC inhibition. Data from our lab identify enzymatic activation of HDAC4 as a driver of HFpEF development. Given that HDAC4 belongs to the class IIa HDAC family (HDAC4, 5, 7, and 9), we investigated whether other family members also contribute to disease progression. We generated mutant mice lacking the specific enzymatic activity of each class IIa HDAC. All mutants exhibited attenuation of diastolic dysfunction under high-fat diet (HFD) and iNOS inhibition (L-NAME), with HDAC4 loss showing the most pronounced reduction in cardiac class IIa HDAC activity and the strongest improvement in diastolic function, highlighting its predominant cardiac role. Loss of HDAC5 improved glucose tolerance and hypertension, while HDAC7 and HDAC9 mutations ameliorated hypertension, implicating these isoforms in metabolic and vascular regulation. Single-cell transcriptomic data corroborate these findings, revealing HDAC4 enrichment in cardiomyocytes, HDAC7 expression in fibroblasts and endothelial cells, and HDAC9 predominantly in endothelial cells and macrophages, while HDAC5 shows highest expression smooth muscle cells. The exact molecular mechanisms underlying class IIa HDAC function in HFpEF are yet to be fully elucidated; however, new findings from our laboratory implicate these enzymes in mitochondrial metabolic reprogramming and macrophage rewiring, providing new paths toward defining their mode of action and the subsequent development of targeted therapies.
