The transcriptional factor Myocyte Enhancer Factor 2 (MEF2) is repressed by class IIa histone deacetylases (HDAC4, HDAC5, HDAC7, and HDAC9). In cardiomyocytes, repression of MEF2 by HDAC4 plays a pivotal role in metabolism. During acute physiological stress such as exercise, Protein Kinase A (PKA) induces ABHD5-mediated proteolysis of HDAC4, generating an N-terminal 201-amino acid fragment (HDAC4-NT). HDAC4-NT is sufficient to repress MEF2; however, its exact mechanism remains unknown. Our research aims to elucidate the mechanism of HDAC4-NT-mediated repression of MEF2 using a domain-specific approach and explore its therapeutic potential. Through MEF2 luciferase assays, we identified domains within HDAC4-NT responsible for MEF2 repression and characterized the biochemical interaction between HDAC4-NT and MEF2 using Co-immunoprecipitation (Co-IP) with mutants. Given MEF2’s role in cardiac metabolism, we examined the therapeutic potential of HDAC4-NT in a murine two-hit model of Heart Failure with preserved Ejection Fraction (HFpEF), induced by a high-fat diet (HFD) and 0.5% N(ω)-nitro-L-arginine methyl ester (L-NAME). Remarkably, mice receiving cardiac-specific HDAC4-NT gene therapy were protected from developing diastolic dysfunction despite increased fat mass, with no difference in lean mass. To further delineate the mechanism, we are currently inducing HFpEF in cardiac-specific Mef2d-deficient mice (Mef2d-cKO) using the same model. Based on this proof of concept, our long-term goal is to develop HDAC4-NT gene therapy as a potent therapeutic strategy for HFpEF. Additionally, HDAC4-NT gene therapy shows efficacy in Heart Failure with reduced Ejection Fraction (HFrEF) models, suggesting potential use in dilated cardiomyopathy (DCM) and pulmonary hypertension-associated right ventricular heart failure (PH-RVHF). These data provide strong support that despite distinct etiologies of HFpEF and HFrEF, there is space for more one-fits-all approaches. My data in concert with findings from the Backs lab, support that both genomic and non-genomic interventions of metabolic programs can overcome cardiac features of HFpEF, offering a new conceptual understanding of its pathomechanisms.
