HDAC inhibition elicits myocardial protective effect through modulation of MKK3/Akt-1

• Published in: PloS one 2013-06, Vol.8 (6), p.e65474-e65474
• Main Authors: Zhao, Ting C, Du, Jianfeng, Zhuang, Shougang, Zhuang, Shugang, Liu, Paul, Zhang, Ling X
• Format: Article
• Language: English
• Subjects: Acetates; Acetylation; Acetylation - drug effects; Adenosine; AKT protein; AKT1 protein; Animals; Biology; Blotting, Western; Chromatin; Disruption; Fluorescent Antibody Technique; Gene expression; Heart; Heart attack; Heart attacks; Heart diseases; Heart rate; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Hospitals; Hydroxamic Acids - pharmacology; Immunoenzyme Techniques; Immunoprecipitation; Inhibition; Ischemia; Kinases; Laboratory animals; Male; Mammals; MAP kinase; MAP Kinase Kinase 3 - metabolism; Mathematics; Medical schools; Medicine; Mice; Mice, Knockout; MKK3 protein; Modulation; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - prevention & control; Myocardial ischemia; Myocardium; Pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Preconditioning; Proteins; Proto-Oncogene Proteins c-akt - physiology; Recovery of function; Reperfusion; Rodents; Signal Transduction - drug effects; Stem cells; Surgery; Trichostatin A; Ventricle; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065474

We and others have demonstrated that HDAC inhibition protects the heart against myocardial injury. It is known that Akt-1 and MAP kinase play an essential role in modulation of myocardial protection and cardiac preconditioning. Our recent observations have shown that Akt-1 was activated in post-myocardial infarction following HDAC inhibition. However, it remains unknown whether MKK3 and Akt-1 are involved in HDAC inhibition-induced myocardial protection in acute myocardial ischemia and reperfusion injury. We sought to investigate whether the genetic disruption of Akt-1 and MKK3 eliminate cardioprotection elicited by HDAC inhibition and whether Akt-1 is associated with MKK3 to ultimately achieve protective effects. Adult wild type and MKK3⁻/⁻, Akt-1⁻/⁻ mice received intraperitoneal injections of trichostatin A (0.1 mg/kg), a potent inhibitor of HDACs. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after twenty four hours to elicit pharmacologic preconditioning. Left ventricular function was measured, and infarct size was determined. Acetylation and phosphorylation of MKK3 were detected and disruption of Akt-1 abolished both acetylation and phosphorylation of MKK3. HDAC inhibition produces an improvement in left ventricular functional recovery, but these effects were abrogated by disruption of either Akt-1 or MKK3. Disruption of Akt-1 or MKK3 abolished the effects of HDAC inhibition-induced reduction of infarct size. Trichostatin A treatment resulted in an increase in MKK3 phosphorylation or acetylation in myocardium. Taken together, these results indicate that stimulation of the MKK3 and Akt-1 pathway is a novel approach to HDAC inhibition -induced cardioprotection.