Acute Inhibition of HDACs after MI Leads to Low Inflammatory Profile: Implications for Post‐MI Angiogenesis

Abstract

IntroductionAlthough the histone deacetylase inhibitors (HDACi) confer protection after myocardial injury (MI), the changes in the profiles of the angiogenic regulators and neoangiogenesis are unknown.HypothesisWe hypothesized that pan‐HDACi treatment confers positive angiogenic responses after MI, thereby improving the myocardial repair process.MethodsAll the mice underwent permanent LAD ligation. The mice were treated with PXD101, a HDACi, for a period of 3 days at a dose of 100 mg/kg, I.P., daily after the creation of MI. Mice were sacrificed after 72 hrs. of MI and the ischemic and non‐ischemic portions of heart tissue were collected. Relative levels of 53 angiogenesis‐related proteins were quantified by using angiogenic arrays. Heart function was evaluated before and after 72 hrs. of MI injury. Markers of inflammatory cells (macrophages and neutrophils) and endothelial progenitor cells (EPCs) were assayed in the ischemic tissues.ResultsPXD101 treatment did not ameliorate heart function after the 72 hrs. of treatment. There were specific changes in the levels of inflammatory markers such as CXCL1 and MCP‐1 after the treatment. Further assaying of various markers revealed that less inflammatory cell presence with moderate changes in the markers of EPCs in the ischemic tissues after the treatment. Deacetylation of non‐histone proteins were implicated in suppression of the inflammatory cell chemoattractants.ConclusionsOur study underscored the role of HDACi in regulation of myocardial angiogenic responses after MI injury. Acute inhibition of HDACs led to lower inflammatory profile. This study has pinpointed underlying epigenetic changes responsible for the neoangiogenesis and tissue regeneration after MI.Support or Funding InformationNIH grants: HL108621, HL074185 and DK104653.