title: Enhanced nitric oxide-mediated autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion.
abstract: Ischemic preconditioning (IPC) protects against liver ischemia/reperfusion (I/R) injury. Autophagy is an essential cytoprotective system that is rapidly activated by multiple stressors. Nitric oxide (NO) acts as an inducer of IPC. We examined the impact of autophagy in liver IPC and its regulation by NO. Male C57BL/6 mice were subjected to 60 min of hepatic ischemia followed by 6 h of reperfusion. IPC was achieved for 10 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. N(ω)-Nitro-l-arginine methyl ester (L-NAME, 15 mg/kg, i.v., all NOS inhibitor) and aminoguanidine (AG, 10 mg/kg, i.v., iNOS inhibitor) were injected 10 min before IPC. SB203580 (10 mg/kg, i.p., p38 inhibitor) was injected 30 min before IPC. I/R increased serum alanine aminotransferase activity. IPC attenuated this increase, which was abolished by L-NAME, but not AG. Microtubule-associated protein-1 light chain 3-II levels increased and p62 protein levels decreased after I/R; these changes were augmented by IPC and abolished by L-NAME. I/R increased liver protein expression of autophagy-related protein (Atg)12-Atg5 complex and lysosome-associated membrane protein-2. IPC augmented the expression of these proteins, which were abolished by L-NAME, but not AG. IPC also augmented the level of phosphorylated p38 MAPK induced by I/R and this phosphorylation was abolished by L-NAME. Our findings suggest that IPC-mediated NO protects against I/R-induced liver injury by enhancing autophagic flux.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Shin
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Kang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: sunmee@skku.edu.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D001343:Autophagy; D002738:Chloroquine / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D006146:Guanidines; D007093:Imidazoles; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011725:Pyridines; D009569:Nitric Oxide; D002738:Chloroquine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester
keywords: Autophagy; Ischemic preconditioning; Liver; Nitric oxide; p38 MAPK