Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in Basal and oxidative environments

Takashi Mamiya, Fumiki Katsuoka, Aki Hirayama, Osamu Nakajima, Akira Kobayashi, Jonathan M. Maher, Hirofumi Matsui, Ichinosuke Hyodo, Masayuki Yamamoto, Tomonori Hosoya

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)331-339
Number of pages9
JournalTohoku Journal of Experimental Medicine
Volume216
Issue number4
DOIs
Publication statusPublished - 2008

Keywords

  • Carbon tetrachloride
  • Heme oxygenase-1
  • In vivo EPR
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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