Peroxynitrite-Induced Neuronal Apoptosis Is Mediated by Intracellular Zinc Release and 12-Lipoxygenase Activation
Peroxynitrite-Induced Neuronal Apoptosis Is Mediated by Intracellular Zinc Release and 12-Lipoxygenase Activation
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DOI：
10.1523/jneurosci.2469-04.2004
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发表时间：
2004-11
期刊：
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通讯作者：
Yumin Zhang;Hong Wang;Jianrong Li;Daniel A. Jimenez;E. Levitan;E. Aizenman;P. Rosenberg
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作者：
Yumin Zhang;Hong Wang;Jianrong Li;Daniel A. Jimenez;E. Levitan;E. Aizenman;P. Rosenberg
过氧亚硝酸盐毒性是中风和神经退行性疾病中神经元损伤的主要原因。过氧亚硝基阴离子引起神经毒性的机制尚不清楚。在这项研究中，我们观察到TPEN [N，N，N′，N′-四（2-吡啶基甲基）乙二胺]，锌螯合剂，保护对外源性以及内源性（NMDA和一氧化氮供体，二乙烯三胺NONOate的共同管理）过氧亚硝酸盐诱导的神经毒性。两种不同的检测细胞内锌释放的方法证明了过亚硝酸盐可以从细胞内储存中释放锌。此外，我们发现，过氧亚硝酸盐的毒性被12-脂氧合酶（12-LOX），p38丝裂原活化蛋白激酶（MAPK）和caspase-3的抑制剂阻断，并与线粒体膜去极化。抑制12-LOX可阻断p38 MAPK和caspase-3的激活。锌本身诱导12-LOX的活化、活性氧（ROS）的产生以及p38 MAPK和caspase-3的活化。这些数据表明，过氧亚硝酸盐触发的细胞死亡途径，其中细胞内锌释放导致12-LOX的激活，ROS积累，p38激活和caspase-3激活。因此，旨在维持细胞内锌稳态或阻断12-LOX活化的疗法可能为治疗炎症、中风和神经退行性疾病提供新途径，其中过氧亚硝酸盐的形成被认为是细胞死亡的重要原因之一。
Peroxynitrite toxicity is a major cause of neuronal injury in stroke and neurodegenerative disorders. The mechanisms underlying the neurotoxicity induced by peroxynitrite are still unclear. In this study, we observed that TPEN [N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine], a zinc chelator, protected against neurotoxicity induced by exogenous as well as endogenous (coadministration of NMDA and a nitric oxide donor, diethylenetriamine NONOate) peroxynitrite. Two different approaches to detecting intracellular zinc release demonstrated the liberation of zinc from intracellular stores by peroxynitrite. In addition, we found that peroxynitrite toxicity was blocked by inhibitors of 12-lipoxygenase (12-LOX), p38 mitogen-activated protein kinase (MAPK), and caspase-3 and was associated with mitochondrial membrane depolarization. Inhibition of 12-LOX blocked the activation of p38 MAPK and caspase-3. Zinc itself induced the activation of 12-LOX, generation of reactive oxygen species (ROS), and activation of p38 MAPK and caspase-3. These data suggest a cell death pathway triggered by peroxynitrite in which intracellular zinc release leads to activation of 12-LOX, ROS accumulation, p38 activation, and caspase-3 activation. Therefore, therapies aimed at maintaining intracellular zinc homeostasis or blocking activation of 12-LOX may provide a novel avenue for the treatment of inflammation, stroke, and neurodegenerative diseases in which the formation of peroxynitrite is thought to be one of the important causes of cell death.