Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in basal and oxidative environments.
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of heme catabolism and has been assumed to be important in cellular response against oxidative stress through modification of the pro-oxidant heme into less toxic catabolites that behave as antioxidants. However, the precise mechanisms involved and the physiological significance of such activity remain to be clarified. To elucidate roles HO-1 plays in vivo, hepatocyte-specific conditional knockout (CKO) mice of HO-1 gene were generated by site-specific recombination using albumin-promoter-driven Cre-loxP system. In livers of HO-1 CKO mice HO-1 protein level decreased to approximately 30% of control mouse livers. The HO-1 CKO mice are viable, exhibit normal growth curves over six months, and show no histological and serological abnormalities. We found that several cytoprotective genes, such as NAD(P)H dehydrogenase quinone 1 and glutathione S-transferase P1, showed markedly elevated expression, suggesting the increase of oxidative stress in HO-1 CKO mice even under quiescent conditions. In vivo electron paramagnetic resonance studies demonstrated that signal decay times of nitroxyl radicals were significantly longer in livers of HO-1 CKO mice than that of control mice, indicating that radical scavenging activity was significantly compromised in the mutant liver. HO-1 CKO mice were susceptible to carbon tetrachloride hepatotoxicity. These results provide the first in vivo evidence that HO-1 acts to protect cells against the oxidative stress in both basal conditions and upon chemical insult.
Mamiya
Takashi
T
Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance, Exploratory Research for Advanced Technology-Japan Science and Technology Corporation, Tsukuba, Japan.
Katsuoka
Fumiki
F
Hirayama
Aki
A
Nakajima
Osamu
O
Kobayashi
Akira
A
Maher
Jonathan M
JM
Matsui
Hirofumi
H
Hyodo
Ichinosuke
I
Yamamoto
Masayuki
M
Hosoya
Tomonori
T
D000818:Animals; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D003001:Cloning, Molecular; D016166:Free Radical Scavengers / Q000378:metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics*; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*
D016166:Free Radical Scavengers; D002251:Carbon Tetrachloride; D051547:Heme Oxygenase-1