Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice

Anne Granger, Ibrahim Abdullah, Faith Huebner, Andrea Stout, Tao Wang, Thomas Huebner, Jonathan A. Epstein, Peter J. Gruber

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetylation of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine model of ischemia-reperfusion, that chemical HDAC inhibitors significantly reduce infarct area, even when delivered 1 h after the ischemic insult. We demonstrate that HDAC inhibitors prevent ischemia-induced activation of gene programs that include hypoxia inducible factor-1α, cell death, and vascular permeability in vivo and in vitro, thus providing potential mechanisms to explain reduced vascular leak and myocardial injury. In vitro, siRNA knockdown experiments implicate HDAC4 as a mediator of the effects in ischemic cardiac myocytes. These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.

Original languageEnglish (US)
Pages (from-to)3549-3560
Number of pages12
JournalFASEB Journal
Volume22
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

Keywords

  • Cardiomyocytes
  • Heart
  • Hypoxia inducible factor 1

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Granger, A., Abdullah, I., Huebner, F., Stout, A., Wang, T., Huebner, T., Epstein, J. A., & Gruber, P. J. (2008). Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB Journal, 22(10), 3549-3560. https://doi.org/10.1096/fj.08-108548