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: Laura Conde de la Rosa, Titia E Vrenken, Rebekka A Hannivoort, Manon Buist-Homan, Rick Havinga, Dirk-Jan Slebos, Henk F Kauffman, Klaas Nico Faber, Peter L M Jansen, Han Moshage
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 44 Issue 7 Pg. 1323-33 (Apr 01 2008) ISSN: 0891-5849 [Print] United States
• PMID: 18206660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• Superoxides
• Carbon Monoxide
• Heme Oxygenase-1
• MAP Kinase Kinase 4
• Caspases

Topics

• Animals
• Apoptosis
• Carbon Monoxide (chemistry)
• Caspases (metabolism)
• Gene Expression Regulation, Enzymologic
• Heme Oxygenase-1 (metabolism)
• Hepatocytes (cytology, metabolism)
• Liver Diseases (pathology)
• MAP Kinase Kinase 4 (metabolism)
• Models, Biological
• Necrosis
• Oxidative Stress
• Protein Isoforms
• Rats
• Superoxides (metabolism)