Limitation of infarct size is a major goal of therapy for acute coronary syndromes. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches may be exploited. Our long-term goal is to understand how epigenetic modulators such as histone deacetylase (HDAC) inhibition can alter the response of the heart to ischemic injury. The specific hypothesis behind the proposed research is that inhibition of HDAC activity in the heart reduces the damage from myocardial ischemia. Furthermore, we hypothesize that this protection is mediated primarily through HDAC2. This hypothesis is based upon the observation by our lab and others that administration of HDAC inhibitors results in significantly smaller infarct size and improved cardiac function in mice. Second, preliminary studies provided with this proposal demonstrate that mice deficient in Hdac2 are also relatively protected from myocardial ischemia. Experimentally, will first establish the role of specific HDAC isoforms following ischemic injury in the mouse by quantifying HDAC enzyme activity and isoform expression in the setting of myocardial ischemic injury in vivo in mice. Second, we will determine if HDAC2 is responsible for the entire effect of HDAC inhibitor reduction of I/R injury by examining infarct size in wild type vs. Hdac2 null mice with and without inhibitors of HDAC activity. We will also determine the cell-type specific contribution of HDAC2-mediated acute reduction in myocardial injury using conditional, tissue-specific Hdac2 gene-targeted mice. Third, we will test the hypothesis that loss of HDAC2 mediates the effect of HDAC inhibitor ischemic protection via HDAC4 by determining if HDAC4 overexpression is sufficient to abrogate the effect of HDAC2-mediated I/R protection. Thus, the focus of this grant is to characterize HDAC isoforms, and specifically the role of HDAC2, in the response to ischemia reperfusion injury in the heart. Accomplishing the aims of this proposal will provide a sound scientific basis for further investigations into this novel method of ischemic injury.
Project Narrative Ischemic heart disease is a major cause of human morbidity and mortality. Based upon our preliminary finding of a dramatic protection of the heart to ischemic injury with HDAC inhibitors, we hope to identify clinically relevant pathways to help this understand the pathological process. Accomplishing the aims of this proposal will provide a direct path to preclinical studies for novel protection of acute coronary syndromes in the heart.
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