Abstract 2277: Inhibition Of Histone Deacetylases Triggers Delayed Pharmacologic Preconditioning Effects Against Myocardial Ischemic Injury
Background: It has been demonstrated that inhibition of histone deacetylases (HDAC) blunts cardiac hypertrophic response. However, it remains unknown about the role of HDACs inhibition in myocardial ischemia and reperfusion injury.
Objective: Our goal was to investigate:
whether HDACs inhibition triggers delayed cardioprotection against myocardial ischemic injury and
whether cardioprotection elicited by HDACs inhibition are associated with p38 activation.
Methods: Mice were treated with either trichostatin A (TSA) (0.1mg/kg, i.p.), a potent inhibitor of HDACs or saline. Twenty four hours later, the hearts were perfused in the Langendorff mode and subjected to 30 min of ischemia followed by 30 min of reperfusion. Left ventricular function was measured and infarct size was determined by triphenyltetrazolium chloride. Western blot was used to detect HDACs 3, 4, and 5 proteins as well as p38 phosphorylation. HDAC and p38 activities were examined following HDACs inhibition.
Results: TSA produced marked improvements in the recovery of left ventricular end-diastolic pressure (LVEDP), LV-dP/dt max, and LV-dP/dt min and rate pressure product as compared to the vehicle group (p<0.05). TSA-induced improvements were completely abrogated by SB203580, a specific inhibitor of p38. TSA treatment led to reduction in myocardial infarct size, which was also blocked by p38 inhibition. Western blot showed abundant HDAC 3, 4 and 5. TSA treatment resulted in significant inhibition of HDAC activity in preconditioned hearts as compared to the vehicle group. Additionally, HDACs inhibition caused a dramatic increase in phosphorylation of p38 and p38 activity. Notably, immunoprecipitation assay revealed that HDACs inhibition resulted in remarkable p38 acetylation at lysine residues.
Conclusion: These results suggest that the direct inhibition of HDACs triggers pharmacologic preconditioning, which is dependent on signaling mechanisms involving p38 activation.