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首页> 美国卫生研究院文献>The Journal of Neuroscience >The Cytosolic Antioxidant Copper/Zinc-Superoxide Dismutase Prevents the Early Release of Mitochondrial Cytochrome c in Ischemic Brain after Transient Focal Cerebral Ischemia in Mice
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The Cytosolic Antioxidant Copper/Zinc-Superoxide Dismutase Prevents the Early Release of Mitochondrial Cytochrome c in Ischemic Brain after Transient Focal Cerebral Ischemia in Mice

机译：细胞溶质抗氧化剂铜/锌超氧化物歧化酶可防止短暂性局灶性脑缺血后缺血性脑线粒体细胞色素c的早期释放

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Release of mitochondrial cytochrome c into the cytosol is a critical step in apoptosis. We have reported that early release of cytochrome c in vivo occurs after permanent focal cerebral ischemia (FCI) and is mediated by the mitochondrial antioxidant manganese superoxide dismutase (SOD). However, the role of reactive oxygen species produced after ischemia–reperfusion in the mitochondrial apoptosis process is still unknown, although overexpression of copper/zinc-SOD (SOD1), a cytosolic isoenzyme, protects against ischemia–reperfusion. We now hypothesize that the overexpression of SOD1 also prevents apoptosis after FCI. To address this issue, we examined the subcellular distribution of the cytochrome c protein in both wild-type mice and in SOD1 transgenic (Tg) mice after transient FCI. Cytosolic cytochrome c was detected as early as 2 hr after reperfusion, and correspondingly, mitochondrial cytochrome c was significantly reduced after FCI. Cytosolic cytochrome c was significantly lower in the SOD1 Tg mice compared with wild types 2 (p < 0.0001) and 4 (p < 0.05) hr after FCI. Apaf-1, which interacts with cytochrome c and activates caspases, was constitutively expressed in both groups of animals, with no alteration after FCI. Double staining with cytochrome c immunohistochemistry and terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling showed a spatial relationship between cytosolic cytochrome c expression and DNA fragmentation. A significant amount of DNA laddering was detected 24 hr after ischemia and was reduced in SOD1 Tg mice. These data suggest that SOD1 blocks cytosolic release of cytochrome c and could thereby reduce apoptosis after transient FCI.
机译：线粒体细胞色素c释放到细胞质中是细胞凋亡的关键步骤。我们已经报道了细胞色素c在体内的早期释放发生在永久性局灶性脑缺血（FCI）之后，并由线粒体抗氧化剂锰超氧化物歧化酶（SOD）介导。然而，尽管过表达铜/锌-SOD（SOD1）（一种胞浆同工酶）可以防止缺血-再灌注，但缺血-再灌注后产生的活性氧在线粒体凋亡过程中的作用仍然未知。我们现在假设SOD1的过表达也可以防止FCI后的细胞凋亡。为了解决此问题，我们检查了瞬时FCI后野生型小鼠和SOD1转基因（Tg）小鼠中细胞色素c蛋白的亚细胞分布。早在再灌注后2小时就检测到了细胞质细胞色素c，相应地，FCI后线粒体细胞色素c明显减少。与野生型2（p <0.0001）和4（p <0.05）野生型相比，SOD1 Tg小鼠的胞质细胞色素c显着降低。与细胞色素c相互作用并激活胱天蛋白酶的Apaf-1在两组动物中均组成性表达，在FCI后未发生改变。细胞色素c免疫组织化学和末端脱氧核苷酸转移酶介导的尿苷5'-三磷酸酯-生物素缺口末端标记的双重染色显示了胞质细胞色素c表达与DNA片段化之间的空间关系。缺血24小时后检测到大量的DNA梯形，并在SOD1 Tg小鼠中减少。这些数据表明，SOD1阻断了细胞色素c的胞质释放，因此可以减少短暂FCI后的细胞凋亡。

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