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

American Journal of Physiology - Lung Cellular and Molecular Physiology - Tập 278 Số 2 - Trang L312-L319 - 2000
Irina Petrache1, Leo E. Otterbein2,1, Jawed Alam3, Gordon Wiegand1, Augustine M.K. Choi4,2
1The Johns Hopkins Medical Institution, Baltimore, Maryland 21205
2Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven 06250;
3Department of Molecular Genetics, Alton Ochsner Medical Foundation, and Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, Louisiana 70121; and
4Connecticut Veterans Affairs HealthCare Service, West Haven, Connecticut 06516;

Tóm tắt

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 1 H-(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.

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American Journal of Physiology - Lung Cellular and Molecular Physiology

Tập 278 Số 2

L312-L319

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