The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells
The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells
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DOI：
10.1074/jbc.m110701200
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发表时间：
2002-03-22
影响因子：
4.8
通讯作者：
Chiueh, CC
中科院分区：
文献类型：
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作者：
Andoh, T;Chock, PB;Chiueh, CC
采用血清剥夺和1-甲基-4-苯基吡啶(MPP+)模型，研究硫氧还蛋白(TRX)对人神经母细胞瘤细胞(SH-SY5Y)的抗凋亡保护作用及预适应诱导的神经保护作用的机制。我们发现SH-SY5Y细胞对氧化应激高度敏感，对细胞外给药和预适应诱导的TRX都有反应。血清剥夺和MPP+使细胞内的羟基自由基、丙二醛和4-羟基-2，3-壬烯醛(HNE)升高，导致线粒体介导的细胞凋亡。亚微摩尔范围内的Trx通过抑制细胞色素c的释放(很可能是通过诱导Bcl2)、抑制Proaspase-9和Proaspase-3的激活以及上调Mn-SOD水平来阻断观察到的细胞凋亡。还原形式的Trx抑制了血清自由基诱导的羟基自由基、脂质过氧化和细胞凋亡，表明Trx过氧化物酶清除了过氧化氢。反义寡核苷酸或TRX还原酶抑制TRX合成可显著降低兴奋效应，这支持TRX参与预适应诱导的神经保护作用。Trx介导的兴奋作用对抗氧化应激诱导的细胞凋亡的作用是显著的。在MPP+诱导的神经毒性中，它诱导LD50发生30倍的变化。
Using models of serum deprivation and 1-methyl-4-phenylpyridinium (MPP+), we investigated the mechanism by which thioredoxin (Trx) exerts its antiapoptotic protection in human neuroblastoma cells (SH-SY5Y) and preconditioning-induced neuroprotection. We showed that SH-SY5Y cells are highly sensitive to oxidative stress and responsive to both extracellularly administered and preconditioning-induced Trx. Serum deprivation and MPP+ produced an elevation in the hydroxyl radicals, malondialdehyde and 4-hydroxy-2,3-nonenal (HNE), causing the cells to undergo mitochondria-mediated apoptosis. Trx in the submicromolar range blocked the observed apoptosis via a multiphasic protection mechanism that includes the suppression of cytochrome c release (most likely via the induction of Bcl-2), the inhibition of procaspase-9 and procaspase-3 activation, and the elevated level of Mn-SOD. The reduced form of Trx suppresses the serum-free-induced hydroxyl radicals, lipid peroxidation, and apoptosis, indicating that H2O2 is removed by Trx peroxidase. The participation of Trx in preconditioning-induced neuroprotection is supported by the observation that inhibition of Trx synthesis with antisense oligonucleotides or of Trx reductase drastically reduced the hormesis effect. This effect of Trx-mediated hormesis against oxidative stress-induced apoptosis is striking. It induced a 30-fold shift in LD50 in the MPP+-induced neurotoxicity.