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: Jane Chun-wen Teng, Helen Kay, Qian Chen, Jovan S Adams, Christopher Grilli, Giuseppe Guglielmello, Christopher Zambrano, Samuel Krass, Adrian Bell, Lindon H Young
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 378 Issue 1 Pg. 1-15 (Jul 2008) ISSN: 0028-1298 [Print] Germany
• PMID: 18496674 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• N-Myr-EAVSLKPT
• N-Myr-HDAPIGYD
• Oligopeptides
• Intercellular Adhesion Molecule-1
• Nitric Oxide
• Hydrogen Peroxide
• Protein Kinase C-epsilon

Topics

• Animals
• Aorta (drug effects, metabolism)
• Cardiotonic Agents (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Hydrogen Peroxide (metabolism)
• Intercellular Adhesion Molecule-1 (drug effects, metabolism)
• Male
• Nitric Oxide (metabolism)
• Oligopeptides (administration & dosage, pharmacology)
• Protein Kinase C-epsilon (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, physiopathology)