BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia
BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia
复制标题
DOI：
10.1073/pnas.261323298
复制
发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
--
作者：
Plesnila, N;Zinkel, S;Moskowitz, MA
线粒体和细胞色素c的释放在脑缺血后神经元和神经胶质细胞的死亡中起作用。在本研究中，我们研究了细胞色素c释放和半胱氨酸天冬氨酸蛋白酶8底物的促凋亡启动子Bid是否在脑内表达，并在体内和体外缺血损伤后被激活，并参与了缺血细胞的死亡。我们在小鼠脑和原代培养的小鼠神经元的胞浆中检测到BID，并通过使用重组caspase 8证明了神经元BID也是Caspase 8的底物。缺氧缺糖2 h后，在caspase8激活的同时，神经元中检测到Bid裂解，但caspase3尚未裂解。BID(-/-)神经元耐缺氧缺糖后死亡，caspase3裂解显著减少，而caspase8裂解与野生型无明显差异。在体内，一过性大脑中动脉闭塞后4h，BID被裂解。在轻度局灶性脑缺血后，BID(-/-)小鼠的脑梗塞体积和细胞色素c释放也较少(分别为-67%和-41%)。这些发现表明，BID和促进caspase激活的线粒体放大途径在缺血性损伤后神经细胞死亡中起重要作用。
Mitochondria and cytochrome c release play a role in the death of neurons and glia after cerebral ischemia. In the present study, we investigated whether BID, a proapoptotic promoter of cytochrome c release and caspase 8 substrate, was expressed in brain, activated after an ischemic insult in vivo and in vitro, and contributed to ischemic cell death. We detected BID in the cytosol of mouse brain and primary cultured mouse neurons and demonstrated, by using recombinant caspase 8, that neuronal BID also is a caspase 8 substrate. After 2 h of oxygen/glucose deprivation, BID cleavage was detected in neurons concurrent with caspase 8 activation but before caspase 3 cleavage. Bid(-/-) neurons were resistant to death after oxygen/glucose deprivation, and caspase 3 cleavage was significantly reduced; however, caspase 8 cleavage did not differ from wild type. In vivo, BID was cleaved 4 h after transient middle cerebral artery occlusion. Infarct volumes and cytochrome c release also were less in Bid(-/-) mice (-67% and -41%, respectively) after mild focal ischemia. These findings suggest that BID and the mitochondrial-amplification pathway promoting caspase activation contributes importantly to neuronal cell death after ischemic insult.