Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain
Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain
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DOI：
10.1046/j.1471-4159.2003.01832.x
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Blomgren, K
中科院分区：
文献类型：
--
作者：
Zhu, CL;Qiu, L;Blomgren, K
凋亡诱导因子（AIF）以不依赖半胱天冬酶的方式触发凋亡。在这里，我们首次报道了AIF参与脑缺血引起的神经元死亡。通过结扎左侧颈动脉并缺氧（7.7%O-2）55分钟，在7日龄大鼠中诱导单侧脑缺氧缺血（HI）。HI后立即检测到线粒体中AIF释放和AIF移位至细胞核，并且仅在受损区域，根据MAP-2的同时丢失来判断。AIF的释放早于细胞色素c的释放。具有AIF阳性核的细胞显示核浓缩和DNA损伤的迹象。AIF阳性细胞核的数量与HI后72 h的梗死体积呈正相关，并且用多半胱氨酸天冬氨酸蛋白酶抑制剂boc-Asp-天冬氨酸（BAF）治疗动物并没有改变这一点。BAF处理降低了caspase-3，-2和9的活性（分别为78%，73%和33%），并阻止了caspase依赖性胞衬蛋白在体内的裂解，但不影响AIF从线粒体释放或阳性核AIF或DNA损伤的频率HI后72小时，表明这些过程发生在一个caspase独立的方式。总之，AIF介导的细胞死亡可能是HI诱导的未成熟脑中神经元丢失的重要机制。
Apoptosis-inducing factor (AIF) triggers apoptosis in a caspase-independent manner. Here we report for the first time involvement of AIF in neuronal death induced by cerebral ischemia. Unilateral cerebral hypoxia-ischemia (HI) was induced in 7-day-old rats by ligation of the left carotid artery and hypoxia (7.7% O-2 ) for 55 min. AIF release from mitochondria and AIF translocation to nuclei was detected immediately after HI, and only in damaged areas, as judged by the concurrent loss of MAP-2. AIF release was detected earlier than that of cytochrome c . Cells with AIF-positive nuclei displayed nuclear condensation and signs of DNA damage. The number of AIF-positive nuclei showed a positive correlation with the infarct volume 72 h post-HI, and this was not changed by treating the animals with boc-Asp-fmk (BAF), a multicaspase inhibitor. BAF treatment reduced the activity of caspase-3, -2 and -9 (78, 73 and 33%, respectively), and prevented caspase-dependent fodrin cleavage in vivo , but did not affect AIF release from mitochondria or the frequency of positive nuclear AIF or DNA damage 72 h post-HI, indicating that these processes occurred in a caspase-independent fashion. In summary, AIF-mediated cell death may be an important mechanism of HI-induced neuronal loss in the immature brain.