Poss K D, Tonegawa S
Howard Hughes Medical Institute, Center for Learning and Memory, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30. doi: 10.1073/pnas.94.20.10925.
Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular antioxidant defense, we analyzed the responses of cells from mice lacking functional Hmox1 to oxidative challenges. Cultured Hmox1(-/-) embryonic fibroblasts demonstrated high oxygen free radical production when exposed to hemin, hydrogen peroxide, paraquat, or cadmium chloride, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide. Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin. Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress.
处于应激状态的哺乳动物细胞会上调血红素加氧酶1(Hmox1;EC 1.14.99.3),该酶可将血红素分解为胆绿素、一氧化碳和游离铁。为评估Hmox1在细胞抗氧化防御中的潜在作用,我们分析了缺乏功能性Hmox1的小鼠细胞对氧化应激的反应。培养的Hmox1(-/-)胚胎成纤维细胞在暴露于血红素、过氧化氢、百草枯或氯化镉时表现出高氧自由基产生,并且它们对血红素和过氧化氢引起的细胞毒性高度敏感。此外,年轻成年Hmox1(-/-)小鼠在内毒素攻击时易发生死亡和肝坏死。我们的体外和体内结果提供了遗传学证据,表明Hmox1的上调是一种在应激期间保护细胞免受氧化损伤的适应性机制。