Wang Chia-Chun, Fang Kuan-Min, Yang Chung-Shi, Tzeng Shun-Fen
Department of Life Sciences, National Cheng Kung University, Tainan City, Taiwan.
J Cell Biochem. 2009 Aug 1;107(5):933-43. doi: 10.1002/jcb.22196.
Astrocytes, the most abundant glial cell population in the central nervous system (CNS), play physiological roles in neuronal activities. Oxidative insult induced by the injury to the CNS causes neural cell death through extrinsic and intrinsic pathways. This study reports that reactive oxygen species (ROS) generated by exposure to the strong oxidizing agent, hexavalent chromium (Cr(VI)) as a chemical-induced oxidative stress model, caused astrocytes to undergo an apoptosis-like cell death through a caspase-3-independent mechanism. Although activating protein-1 (AP-1) and NF-kappaB were activated in Cr(VI)-primed astrocytes, the inhibition of their activity failed to increase astrocytic cell survival. The results further indicated that the reduction in mitochondrial membrane potential (MMP) was accompanied by an increase in the levels of ROS in Cr(VI)-primed astrocytes. Moreover, pretreatment of astrocytes with N-acetylcysteine (NAC), the potent ROS scavenger, attenuated ROS production and MMP loss in Cr(VI)-primed astrocytes, and significantly increased the survival of astrocytes, implying that the elevated ROS disrupted the mitochondrial function to result in the reduction of astrocytic cell viability. In addition, the nuclear expression of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) was observed in Cr(VI)-primed astrocytes. Taken together, evidence shows that astrocytic cell death occurs by ROS-induced oxidative insult through a caspase-3-independent apoptotic mechanism involving the loss of MMP and an increase in the nuclear levels of mitochondrial pro-apoptosis proteins (AIF/EndoG). This mitochondria-mediated but caspase-3-independent apoptotic pathway may be involved in oxidative stress-induced astrocytic cell death in the injured CNS.
星形胶质细胞是中枢神经系统（CNS）中数量最多的胶质细胞群，在神经元活动中发挥生理作用。中枢神经系统损伤引起的氧化损伤通过外在和内在途径导致神经细胞死亡。本研究报道，作为化学诱导氧化应激模型，暴露于强氧化剂六价铬（Cr(VI)）产生的活性氧（ROS）通过不依赖半胱天冬酶-3的机制导致星形胶质细胞发生凋亡样细胞死亡。尽管激活蛋白-1（AP-1）和核因子κB在Cr(VI)预处理的星形胶质细胞中被激活，但抑制它们的活性并不能提高星形胶质细胞的存活率。结果进一步表明，Cr(VI)预处理的星形胶质细胞中线粒体膜电位（MMP）的降低伴随着ROS水平的升高。此外，用强效ROS清除剂N-乙酰半胱氨酸（NAC）预处理星形胶质细胞，可减弱Cr(VI)预处理的星形胶质细胞中ROS的产生和MMP的丧失，并显著提高星形胶质细胞的存活率，这意味着升高的ROS破坏了线粒体功能，导致星形胶质细胞活力降低。此外，在Cr(VI)预处理的星形胶质细胞中观察到凋亡诱导因子（AIF）和核酸内切酶G（EndoG）的核表达。综上所述，有证据表明，星形胶质细胞死亡是由ROS诱导的氧化损伤通过不依赖半胱天冬酶-3的凋亡机制发生的，该机制涉及MMP的丧失和线粒体促凋亡蛋白（AIF/EndoG）核水平的增加。这种线粒体介导但不依赖半胱天冬酶-3的凋亡途径可能参与了损伤中枢神经系统中氧化应激诱导的星形胶质细胞死亡。
