title: HDAC inhibition elicits myocardial protective effect through modulation of MKK3/Akt-1.
abstract: 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.
authors.affiliation: Cardiovascular Research laboratory, Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, United States of America. tzhao@bu.edu
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Du
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.forename: Shugang
authors.initials: S
authors.lastname: Zhuang
authors.forename: Paul
authors.initials: P
authors.lastname: Liu
authors.forename: Ling X
authors.initials: LX
authors.lastname: Zhang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse; D006655:Histone Deacetylases