Signaling of cell death and cell survival following focal cerebral ischemia: Life and death struggle in the penumbra
Signaling of cell death and cell survival following focal cerebral ischemia: Life and death struggle in the penumbra
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DOI：
10.1093/jnen/62.4.329
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发表时间：
2003-04-01
影响因子：
3.2
通讯作者：
Planas, AM
中科院分区：
文献类型：
--
作者：
Ferrer, I;Planas, AM
大脑中动脉闭塞（MCAO）导致的局灶性缺血会在梗死核心处引发坏死，并激活半暗带中细胞死亡和细胞存活的复杂信号通路。近期研究表明，在成年大鼠和小鼠短暂性大脑中动脉闭塞所致的几种局灶性脑缺血范例中，半胱天冬酶介导的细胞死亡的外源性和内源性通路被激活，以及不依赖半胱天冬酶的细胞凋亡信号通路也被激活。外源性通路（细胞死亡受体通路）是在Fas受体与Fas配体（Fas - L）结合后被激活的；局灶性缺血后已显示Fas和Fas - L表达增加。此外，在表达突变（无功能）Fas的小鼠中，局灶性缺血显著减少。在半暗带中已观察到半胱天冬酶 - 1、 - 3、 - 8和 - 9以及裂解的半胱天冬酶 - 8的表达增加。局灶性缺血后内源性（线粒体）通路的激活是由Bax转位到线粒体膜并与Bcl - 2及Bcl - 2家族的其他成员竞争引发的，随后细胞色素c释放到细胞质中。Bcl - 2的过度表达会减小梗死面积。细胞色素c与Apaf - 1和dATP结合，并在凋亡小体中招募并裂解前体半胱天冬酶 - 9。半胱天冬酶 - 8和半胱天冬酶 - 9都会激活半胱天冬酶 - 3以及其他半胱天冬酶，半胱天冬酶 - 3进而会将包括DNA修复酶多聚（ADP - 核糖）聚合酶（PARP）在内的几种关键底物裂解成89和28 kDa的片段。抑制半胱天冬酶 - 3会减小梗死面积，进一步证明了短暂性大脑中动脉闭塞后半胱天冬酶 - 3被激活。此外，半胱天冬酶 - 8会裂解Bid，其截短形式能够转位到线粒体并诱导细胞色素c释放。在Bid缺陷小鼠中，脑梗死体积大大减小，这表明局灶性缺血后细胞死亡受体激活了线粒体通路。近期研究还显示了其他因子从线粒体释放；Smac/DIABLO（Smac：半胱天冬酶的第二种线粒体激活剂；DIABLO：低等电点的直接IAP结合蛋白）与X连锁凋亡抑制蛋白（XIAP）结合并中和其作用。最后，凋亡诱导因子（AIF）在局灶性缺血后转位到线粒体和细胞核，并导致周边染色质凝聚和大规模DNA链断裂，从而引发不依赖半胱天冬酶的细胞凋亡死亡通路。对半暗带中促凋亡和促存活信号的描述不仅可以增进对这一过程的理解，还有助于使针对梗死核心周边以减少脑损伤为目标的策略合理化。
Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases. which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly (ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition. caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome e release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pl) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands. thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at tire periphery of the infarct core.