Abstract 443: Class I Histone Deacetylases Mediate Cardiac I/R Injury and Modify the Mitochondrial Acetylome

Abstract

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, a significant amount of damage occurs as a result of reperfusion itself. The role of epigenetic enzymes in modulating this damage has become an area of interest in basic cardiac research. Previously, we have shown that pharmacological inhibition of the class I histone deacetylases (HDACs) with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Interestingly, we have also observed that class I HDAC inhibition during 60 minutes of reperfusion alone is sufficient to protect cardiac tissue viability following I/R injury. Therefore, we hypothesized that class I HDACs mediate reperfusion injury by modulating acetylation of non-canonical pathways. To examine this, hearts from male Sprague-Dawley rats were subjected to I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to the mitochondrial fraction of cardiac tissue homogenates and may modulate mitochondrial acetylation by direct or indirect mechanisms. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.