DeltaPKC-mediated activation of epsilonPKC in ethanol-induced cardiac protection from ischemia.
Previous studies have demonstrated that acute ethanol exposure induces activation of delta protein kinase C (deltaPKC) and epsilonPKC, and mimics ischemic preconditioning via epsilonPKC activation. However, the role of deltaPKC isozyme in ischemia and reperfusion is still controversial. Here, we investigated the role of deltaPKC in ethanol-induced cardioprotection using a selective deltaPKC activator (psideltaRACK), or inhibitor (deltaV1-1), and a selective epsilonPKC inhibitor (epsilonV1-2) in isolated mouse hearts. Mice were injected intraperitoneally or by gavage with ethanol, regulators of delta and epsilonPKC or an adenosine A1 receptor blocker (DPCPX). Isolated perfused mouse hearts were subjected to a 30-min global ischemia and a 120-min reperfusion, ex vivo. Injection of 0.5 g/kg ethanol 1 h, but not 10 min, before ischemia reduced infarct size and CPK release. Pretreatment with epsilonV1-2 abolished this ethanol-induced cardioprotection. Pretreatment with deltaV1-1 induced cardioprotection when injected with ethanol (0.5 g/kg) 10 min before ischemia, but deltaV1-1 partly inhibited ethanol-induced cardioprotection when injected with ethanol 1-h before the onset of ischemia. psideltaRACK injection 1 h, but not 10 min, before ischemia induced cardioprotection and translocation of epsilonPKC from the cytosol to the particulate fraction. Pretreatment with DPCPX or epsilonV1-2 inhibited psideltaRACK-induced cardioprotection and translocation of epsilonPKC. Therefore, activation of deltaPKC-induced by ethanol or by the deltaPKC activator is cardioprotective, provided that sufficient time passes to allow deltaPKC-induced activation of epsilonPKC, an A1 adenosine receptor-dependent process.
Department of Molecular Pharmacology, Stanford University School of Medicine, CCSR, Room 3145A, 269, Campus Drive, Stanford, CA 94305-5174, USA.
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Inagaki
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Mochly-Rosen
D000818:Animals; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000378:metabolism / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017202:Myocardial Ischemia / Q000517:prevention & control*; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control; D013347:Subcellular Fractions / Q000378:metabolism
D020536:Enzyme Activators; D007527:Isoenzymes; D000431:Ethanol; D048052:Mitogen-Activated Protein Kinase 3