title: Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform.
abstract: Most chronic liver diseases are accompanied by oxidative stress, which may induce apoptosis in hepatocytes and liver injury. Oxidative stress induces heme oxygenase-1 (HO-1) expression. This stress-responsive cytoprotective protein is responsible for heme degradation into carbon monoxide (CO), free iron, and biliverdin. CO is an important intracellular messenger; however, the exact mechanisms responsible for its cytoprotective effect are not yet elucidated. Thus, we investigated whether HO-1 and CO protect primary hepatocytes against oxidative-stress-induced apoptosis. In vivo, bile duct ligation was used as model of chronic liver disease. In vitro, primary hepatocytes were exposed to the superoxide anion donor menadione in a normal and in a CO-- containing atmosphere. Apoptosis was determined by measuring caspase-9, -6, -3 activity and poly(ADP-ribose) polymerase cleavage, and necrosis was determined by Sytox green staining. The results showed that (1) HO-1 is induced in chronic cholestatic liver disease, (2) superoxide anions time- and dose-dependently induce HO-1 activity, (3) HO-1 overexpression inhibits superoxide-anions-induced apoptosis, and (4) CO blocks superoxide-anions-induced JNK phosphorylation and caspase-9, -6, -3 activation and abolishes apoptosis but does not increase necrosis. We conclude that HO-1 and CO protect primary hepatocytes against superoxide-anions-induced apoptosis partially via inhibition of JNK activity. CO could represent an important candidate for the treatment of liver diseases.
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. lcondedelarosa@gmail.com
authors.forename: Laura
authors.initials: L
authors.lastname: Conde de la Rosa
authors.forename: Titia E
authors.initials: TE
authors.lastname: Vrenken
authors.forename: Rebekka A
authors.initials: RA
authors.lastname: Hannivoort
authors.forename: Manon
authors.initials: M
authors.lastname: Buist-Homan
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Slebos
authors.forename: Henk F
authors.initials: HF
authors.lastname: Kauffman
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.forename: Han
authors.initials: H
authors.lastname: Moshage
mesh_terms: D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000737:chemistry*; D020169:Caspases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008107:Liver Diseases / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008954:Models, Biological; D009336:Necrosis; D018384:Oxidative Stress; D020033:Protein Isoforms; D051381:Rats; D013481:Superoxides / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D013481:Superoxides; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D048670:MAP Kinase Kinase 4; D020169:Caspases