Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts.
Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts.
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发表时间：
2000
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通讯作者：
I. Petrache;L. Otterbein;J. Alam;G. Wiegand;A. Choi
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作者：
I. Petrache;L. Otterbein;J. Alam;G. Wiegand;A. Choi
血红素加氧酶(HO)-1催化血红素的氧化裂解，生成等摩尔胆绿素、铁和一氧化碳。HO-1是一种应激反应蛋白，其诱导与抵抗氧化应激有关。保护作用的机制(S)尚未完全阐明，尽管有人认为一个或多个催化副产物直接或间接地提供抗氧化功能。HO-1在细胞程序性死亡中的可能作用提出了HO-1参与细胞凋亡的问题。利用四环素调控的表达系统，我们在这里证明了有条件地过表达HO-1可以阻止肿瘤坏死因子-α诱导的小鼠L929成纤维细胞的凋亡。在HO活性的特异性抑制剂TIN原卟啉存在的情况下，以及在过度表达反义HO-1的细胞中，没有观察到对细胞凋亡的抑制。有趣的是，外源性低浓度的一氧化碳也能阻止肿瘤坏死因子-α诱导的L929成纤维细胞的凋亡。一氧化碳靶酶鸟苷环化酶抑制剂1H-(1，2，4)恶二唑(4，3-a)喹恶灵-1-酮可逆转HO-1过表达对肿瘤坏死因子-α诱导的细胞凋亡的抑制作用。综上所述，我们的数据提示HO-1的抗凋亡作用可能是通过一氧化碳介导的。
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.