Nitric oxide mitigates apoptosis in human endothelial cells induced by 9,10-phenanthrenequinone: Role of proteasomal function
Nitric oxide mitigates apoptosis in human endothelial cells induced by 9,10-phenanthrenequinone: Role of proteasomal function
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DOI：
10.1016/j.tox.2009.12.015
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发表时间：
2010-02-09
期刊：
影响因子：
4.5
通讯作者：
Hara, Akira
中科院分区：
文献类型：
--
作者：
Matsunaga, Toshiyuki;Arakaki, Marina;Hara, Akira
人们普遍认为一氧化氮（NO）可抑制内皮细胞的氧化损伤，但对其在柴油机尾气颗粒中主要醌成分9,10-菲醌（9,10-PQ）诱导细胞凋亡中的病理生理学作用知之甚少。在这里，我们研究了人主动脉内皮细胞中 NO 水平的变化以及 NO 在 9,10-PQ 启动的细胞凋亡信号传导的每个步骤中的影响。用 9,10-PQ 处理引起了钟形 NO 的产生，这可能是由于内皮 NO 合酶的活性形式增加所致。外源NO预处理降低了细胞对9,10-PQ的敏感性，并从暴露于高浓度9,10-PQ期间诱导的细胞凋亡信号传导（活性氧生成、谷胱甘肽消耗和半胱天冬酶激活）中恢复。此外，抑制内源性 NO 的产生会增强 9,10-PQ 的毒性。有趣的是，9,10-PQ 处理导致蛋白酶体活性显着降低，而 NO 和细胞可渗透的 cGMP 类似物部分消除了蛋白酶体活性。这些结果表明，氧化应激引起的蛋白酶体功能障碍参与了 9,10-PQ 诱导的细胞凋亡信号传导，并通过 cGMP 依赖性途径被 NO 改善，从而表明 NO 在 9,10-PQ 引起的血管损伤中具有保护作用。 (C) 2009 Elsevier Ireland Ltd. 保留所有权利。
It has been widely recognized that nitric oxide (NO) suppresses oxidative damage of endothelial cell, but little is known about its pathophysiological role in apoptotic induction by 9,10-phenanthrenequinone (9,10-PQ), a major quinone component in diesel exhaust particles. Here, we have investigated the change in NO level in human aortic endothelial cells and the effect of NO in each step of apoptotic signaling initiated by 9,10-PQ Treatment with 9,10-PQ evoked a bell-shaped production of NO, which was presumably due to increase in an active form of endothelial NO synthase. Pretreatment with exogenous NO decreased the susceptibility of the cells to 9,10-PQ and retrieved from apoptotic signaling (reactive oxygen species generation, glutathione depletion and caspase activation) induced during exposure to high concentrations of 9,10-PQ. In addition, inhibition of endogenous NO production augmented the toxicity of 9,10-PQ. Interestingly, the 9,10-PQ treatment resulted in marked decreases in the proteasomal activities, which were partially abrogated by NO and a cell-permeable cGMP analog. These results indicate that proteasomal dysfunction by oxidative stress participates in the 9,10-PQ-induced apoptotic signaling and is ameliorated by NO via a cGMP-dependent pathway, thereby suggesting the protective role of NO in vascular damage caused by 9,10-PQ. (C) 2009 Elsevier Ireland Ltd. All rights reserved.