Isoform-selective HDAC Inhibitor Mocetinostat (MGCD0103) Alleviates Myocardial Ischemia/Reperfusion Injury via Mitochondrial Protection through the HDACs/CREB/PGC-1α Signaling Pathway.

Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial ischemia/reperfusion injury (MIRI), cardiac hypertrophy, ventricular remodeling, myocardial fibrosis. Inhibition of histone deacetylases, especially class-I HDACs, is potent to protection of ischemic myocardium after ischemia/reperfusion. Herein, we examine whether mocetinostat (MGCD0103, MOCE), a class-I selective HDAC inhibitor in phase-II clinical trial, conducts cardioprotection under ischemia/reperfusion (I/R) in vivo and vitro, if so, reveal its potential pharmacological mechanism to provide an experimental and theoretical basis for mocetinostat usage in a clinical setting. HCMs were exposed to hypoxia and reoxygenation (H/R), with or without mocetinostat treatment. H/R reduced mitochondrial membrane potential (MMP) and induced HCMs apoptosis. Mocetinostat pre-treatment reversed these H/R-induced mitochondrial damage and cellular apoptosis and upregulated CREB, p-CREB and PGC-1α in HCMs during H/R. Transfection with siRNA against PGC-1α or CREB abolished the protective effects of mocetinostat on cardiomyocytes undergoing H/R. In vivo, mocetinostat was demonstrated to protect myocardial injury posed by myocardial ischemia/reperfusion (I/R) via activation of CREB and upregulation of PGC-1α. Mocetinostat (MGCD0103) can protect myocardium from ischemia/reperfusion injury through mitochondrial protection mediated by CREB/PGC-1α pathway. Therefore, activation of the CREB/PGC-1α signaling pathway via inhibition of Class-I HDACs may be a promising new therapeutic strategy for alleviating myocardial reperfusion injury.