Trichostatin A Ameliorates Myocardial Ischemia/Reperfusion Injury Through Inhibition of Endoplasmic Reticulum Stress-induced Apoptosis

Abstract

Trichostatin A (TSA) is a potent histone deacetylase inhibitor and widely used as a promising anticancer agent. Recently, a novel insight for TSA has been shown to protect the heart from ischemia/reperfusion (I/R) injury in mice, but the underlying mechanism remains unclear. The purpose of this study is to investigate whether TSA can influence endoplasmic reticulum stress (ERS) and whether its cardioprotective effect is mediated by inhibiting myocardial ERS-induced apoptosis in rats. Male Wistar rats were used and pretreated with saline or TSA (0.05, 0.1 and 0.2 mg·kg(-1)) once daily i.p. for 5 days. I/R model was established by occlusion/release of the left anterior descending coronary artery. TSA significantly reduced myocardial infarct size and plasma activities of lactate dehydrogenase and creatine kinase in a dose-dependent manner in rats. Accompanied by the reduced injury, TSA also markedly reduced I/R-induced myocardial apoptosis (30 min/24 h) by the TUNEL assay. In addition, increased expression of glucose-regulated protein 78 (an ERS marker) by Western blot showed the effects of TSA on ERS. Induction of C/EBP homologous protein (CHOP), a critical mediator for ERS-induced apoptosis, was attenuated by TSA after reperfusion for 6 h and 24 h. Our findings showed that inhibition of histone deacetylase ameliorated I/R-induced myocardial injury in vivo and for the first time provided the evidence that suppression of CHOP expression and attenuation of the CHOP-induced apoptosis may contribute to the cardioprotection of TSA against myocardial I/R injury.