Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform.
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.
Conde de la Rosa
Laura
L
Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. lcondedelarosa@gmail.com
Vrenken
Titia E
TE
Hannivoort
Rebekka A
RA
Buist-Homan
Manon
M
Havinga
Rick
R
Slebos
Dirk-Jan
DJ
Kauffman
Henk F
HF
Faber
Klaas Nico
KN
Jansen
Peter L M
PL
Moshage
Han
H
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
D020033:Protein Isoforms; D013481:Superoxides; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D048670:MAP Kinase Kinase 4; D020169:Caspases