title: Differential consequences of protein kinase C activation during early and late hepatic ischemic preconditioning.
abstract: Activation of protein kinase C (PKC) has been implicated in the protection of ischemic preconditioning (IPC), but the exact role of PKC in early and late hepatic IPC is still unclear. The present study was conducted in order to investigate the differential role of PKC during early and late hepatic IPC. Rats were subjected to 90 min of partial hepatic ischemia followed by 3 (early IPC) and 24 h (late IPC) of reperfusion. IPC was induced by 10 min of ischemia following 10 min of reperfusion prior to sustained ischemia, and chelerythrine, a PKC inhibitor, was injected 10 min before IPC (5 mg/kg, i.v.). Chelerythrine abrogated the protection of early IPC, as indicated by increased serum aminotransferase activities and decreased hepatic glutathione content. While the IPC-treated group showed a few apoptotic cell deaths during both phases, chelerythrine attenuated these changes only at late IPC and limited IPC-induced inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) overexpression. Membrane translocation of PKC-δ and -ε during IPC was blocked by chelerythrine. Our results suggest that PKC might play a differential role in early and late IPC; activation of PKC-δ and -ε prevents necrosis in early IPC through preservation of redox state and prevents apoptosis in late IPC with iNOS and HO-1 induction. Therefore, PKC represents a promising target for hepatocyte tolerance to ischemic injury, and understanding the differential role of PKC in early and late IPC is important for clinical application of IPC.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.
authors.forename: Nari
authors.initials: N
authors.lastname: Yun
authors.forename: Sung-Hwa
authors.initials: SH
authors.lastname: Kim
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053119:Benzophenanthridines / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008107:Liver Diseases / Q000503:physiopathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D000098:Acetophenones; D053119:Benzophenanthridines; D001578:Benzopyrans; D045304:Cytochromes c; C085746:rottlerin; C016299:chelerythrine; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D048051:p38 Mitogen-Activated Protein Kinases