Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin.
Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin.
复制标题
硫氧还蛋白在一氧化氮依赖性预处理诱导的 MPTP 神经毒素耐受中的作用。
DOI：
10.1016/j.taap.2005.03.020
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发表时间：
2005
影响因子：
3.8
通讯作者：
Chock,PBoon
中科院分区：
文献类型：
--
作者：
Chiueh,ChuangC;Andoh,Tsugunobu;Chock,PBoon
缺血预处理应激可诱导兴奋效应，这是一种应激耐受。除预适应外，还可通过其他方法诱导，如气体麻醉剂。预处理机制，这可能是通过重新编程生存基因和蛋白质介导的，是模糊的。已知的神经毒物1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）在预处理的小鼠中引起较少的神经毒性。药理学证据表明，NO-cGMP-PKG（蛋白激酶G）信号通路可能介导预适应现象。我们建立了一个人SH-SY 5 Y细胞模型，用于研究短暂2小时血清剥夺引起的亚致死预处理应激后NO介导的信号通路、基因调控和蛋白表达。预处理的人SH-SY 5 Y细胞对致死血清剥夺和1-甲基-4-苯基吡啶（MPP+）引起的严重氧化应激和凋亡具有更强的抵抗力。血清戒断引起的亚致死和致死性氧化应激增加神经元型一氧化氮合酶（nNOS/NOS 1）的表达和NO水平在相似的程度。除自由基清除剂外，抑制nNOS、鸟苷酸环化酶和PKG可阻断预处理诱导的兴奋效应。S-亚硝基硫醇和6-Br-cGMP产生模拟预处理耐受作用的细胞保护作用。有两种不同的cGMP介导的生存途径：（i）上调氧化还原蛋白硫氧还蛋白（Trx），以提高线粒体抗氧化蛋白锰超氧化物歧化酶（MnSOD）和抗凋亡蛋白Bcl-2的水平，以及（ii）激活线粒体ATP敏感性钾通道[K（ATP）]。Trx预处理诱导的MPP+耐受性增加，这被Trx mRNA反义寡核苷酸和Trx还原酶抑制剂阻断。结论：Trx在NO依赖性MPTP/MPP+预处理兴奋效应中起关键作用。
Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of NO–cGMP–PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-mehtyl-4-phenylpyridinium (MPP+). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP+, which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in NO-dependent preconditioning hormesis against MPTP/MPP+.