title: Participation of protein kinase C in the activation of Nrf2 signaling by ischemic preconditioning in the isolated rabbit heart.
abstract: Activation of protein kinase C (PKC) is a critical intracellular signaling triggered by ischemic preconditioning (IPC), but the precise mechanisms underlying the actions of PKC in IPC-mediated cardioprotection remain unclear. Here, we investigated the role of PKC activation on the antioxidant activity by IPC in rabbit hearts. Isolated rabbit hearts were subjected to 60 min of global ischemia by cold cardioplegic arrest (4 °C) and 60 min of reperfusion (37 °C). IPC was induced by three cycles of 2-min ischemia following 3 min of reperfusion (37 °C) before cardioplegic arrest. IPC resulted in a better recovery of mechanical function, increased tissue reduced glutathione-to-oxidized glutathione ratio (GSH/GSSG), superoxide dismutase and catalase content, and decreased tissue malondialdehyde (MDA) content compared to control hearts subjected to 60 min of cardioplegic ischemia and 60 min of reperfusion. IPC also significantly induced activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inductions of antioxidant genes heme oxygenase-1 (HO-1) and manganese superoxide dismutase (MnSOD). Injection of phorbol 12-myristate 13 acetate, an activator of PKC, before cardioplegic ischemia induced translocation of PKC-δ and -ε isoforms to membrane fraction, nuclear accumulation of Nrf2, and conferred cardioprotection similar to IPC. Polymyxin B, an inhibitor of PKC, blocked the membrane translocation of PKC-δ and -ε during IPC, inhibited Nrf2 nuclear accumulation, and significantly diminished the IPC-induced cardioprotection when administrated before IPC. These results indicate that the activation of PKC induces the translocation of Nrf2 and the enhancement of endogenous antioxidant defenses in the IPC hearts and suggest that PKC may target Nrf2 to confer cardioprotection.
authors.affiliation: Department of Cardiac Surgery, Zhengzhou University College of Medicine, Zhengzhou 450052, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Xiao
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yao
authors.forename: Genshang
authors.initials: G
authors.lastname: Zhao
authors.forename: Xianen
authors.initials: X
authors.lastname: Fa
authors.forename: Jianli
authors.initials: J
authors.lastname: Niu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002314:Cardioplegic Solutions / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D003331:Coronary Vessels / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D011112:Polymyxin B / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D021381:Protein Transport; D011817:Rabbits; D013482:Superoxide Dismutase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D000975:Antioxidants; D002314:Cardioplegic Solutions; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D005978:Glutathione; D011112:Polymyxin B; D013755:Tetradecanoylphorbol Acetate