Heme oxygenase-1 inhibits TNF-α-induced apoptosis in cultured fibroblasts

Irina Petrache, Leo E. Otterbein, Jawed Alam, Gordon W. Wiegand, Augustine M.K. Choi

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

Heme oxygenase (HO)-1 catalyzes the oxidative cleavage of heme to yield equimolar amounts of biliverdin, iron, and carbon monoxide. HO-1 is a stress response protein, the induction of which is associated with protection against oxidative stress. The mechanism(s) of protection is not completely elucidated, although it is suggested that one or more of the catalytic by- products provide antioxidant functions either directly or indirectly. The involvement of reactive oxygen species in apoptosis raised the question of a possible role for HO-1 in programmed cell death. Using the tetracycline- regulated expression system, we show here that conditional overexpression of HO-1 prevents tumor necrosis factor-α-induced apoptosis in murine L929 fibroblasts. Inhibition of apoptosis was not observed in the presence of tin protoporphyrin, a specific inhibitor of HO activity, and in cells overexpressing antisense HO-1. Interestingly, exogenous administration of a low concentration of carbon monoxide also prevented tumor necrosis factor- α-induced apoptosis in L929 fibroblasts. Inhibition of tumor necrosis factor-α-induced apoptosis by HO-1 overexpression was reversed by 1H- (1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of guanylate cyclase, which is a target enzyme for carbon monoxide. Taken together, our data suggest that the antiapoptotic effect of HO-1 may be mediated via carbon monoxide.

Original languageEnglish (US)
Pages (from-to)L312-L319
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume278
Issue number2 22-2
DOIs
StatePublished - Feb 2000

Keywords

  • Carbon monoxide
  • Oxidants
  • Programmed cell death
  • Reactive oxygen species
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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