Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts.
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-alpha-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-alpha-induced apoptosis in L929 fibroblasts. Inhibition of tumor necrosis factor-alpha-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.
Petrache
I
I
The Johns Hopkins Medical Institution, Baltimore, Maryland 21205, USA.
Otterbein
L E
LE
Alam
J
J
Wiegand
G W
GW
Choi
A M
AM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008565:Membrane Proteins; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013752:Tetracycline