Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform.
Publication year
2008Source
Free Radical Biology and Medicine, 44, 7, (2008), pp. 1323-33ISSN
Publication type
Article / Letter to editor
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Organization
Physiology
Journal title
Free Radical Biology and Medicine
Volume
vol. 44
Issue
iss. 7
Page start
p. 1323
Page end
p. 33
Subject
IGMD 9: Renal disorder; NCMLS 2: Metabolism, transport and motion; UMCN 5.4: Renal disordersAbstract
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.
This item appears in the following Collection(s)
- Academic publications [238441]
- Faculty of Medical Sciences [90373]
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