title: Mechanisms related to the cardioprotective effects of protein kinase C epsilon (PKC epsilon) peptide activator or inhibitor in rat ischemia/reperfusion injury.
abstract: The role of protein kinase C epsilon (PKC epsilon) in polymorphonuclear leukocyte (PMN)-induced myocardial ischemia/reperfusion (MI/R) injury and novel-related mechanisms, such as regulation of vascular endothelium nitric oxide (NO) and hydrogen peroxide (H2O2) release from blood vessels, have not been previously evaluated. A cell-permeable PKC epsilon peptide activator (1-10 microM) significantly increased endothelial NO release from non-ischemic rat aortic segments (p < 0.01). By contrast, PKC epsilon peptide inhibitor (1-10 microM) dose-dependently decreased NO release (p < 0.01). Then, these corresponding doses of PKC epsilon activator or inhibitor were examined in MI/R. The PKC epsilon inhibitor (5 microM given during reperfusion, n=6) significantly attenuated PMN-induced postreperfused cardiac contractile dysfunction and PMN adherence/infiltration (both p < 0.01), and expression of intracellular adhesion molecule-1 (ICAM-1; p < 0.05). By contrast, only PKC epsilon activator pretreated hearts (5 muM PKC epsilon activator given before ischemia (PT), n = 6), not PKC epsilon activator given during reperfusion (5 microM, n=6) exerted significant cardioprotection (p < 0.01). Moreover, the NO synthase inhibitor, N(G)-nitro-L: -arginine methyl ester, did not block the cardioprotection of PKC epsilon inhibitor, whereas it completely abolished the cardioprotective effects of PKC epsilon activator PT. In addition, PKC epsilon inhibitor (0.4 mg/kg) significantly decreased H(2)O(2) release during reperfusion in a femoral I/R model (p < 0.01). Therefore, the cardioprotection of PKC epsilon inhibitor maybe related to attenuating ICAM-1 expression and H2O2 release during reperfusion. By contrast, the cardioprotective effects of PKC epsilon activator PT may be mediated by enhancing vascular endothelial NO release before ischemia.
authors.affiliation: Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131-1694, USA.
authors.forename: Jane Chun-wen
authors.initials: JC
authors.lastname: Teng
authors.forename: Helen
authors.initials: H
authors.lastname: Kay
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Jovan S
authors.initials: JS
authors.lastname: Adams
authors.forename: Christopher
authors.initials: C
authors.lastname: Grilli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guglielmello
authors.forename: Christopher
authors.initials: C
authors.lastname: Zambrano
authors.forename: Samuel
authors.initials: S
authors.lastname: Krass
authors.forename: Adrian
authors.initials: A
authors.lastname: Bell
authors.forename: Lindon H
authors.initials: LH
authors.lastname: Young
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051744:Protein Kinase C-epsilon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D002316:Cardiotonic Agents; C533725:N-Myr-EAVSLKPT; C533726:N-Myr-HDAPIGYD; D009842:Oligopeptides; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D051744:Protein Kinase C-epsilon