title: gp-91 mediates histone deacetylase inhibition-induced cardioprotection.
abstract: We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91(-)(/-) mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1 mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pre-treatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91(+/+) cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91(phox)-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91(+/+) cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect.
authors.affiliation: Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, RI 02908, USA. tzhao@rwmc.org
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.forename: Ling X
authors.initials: LX
authors.lastname: Zhang
authors.forename: Guangmao
authors.initials: G
authors.lastname: Cheng
authors.forename: Jun T
authors.initials: JT
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002316:Cardiotonic Agents / Q000378:metabolism*; D002470:Cell Survival; D006321:Heart / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology
chemical_list: D002316:Cardiotonic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C012589:trichostatin A; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D006655:Histone Deacetylases