Laboratory of Biochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Toxicology. 2010 Feb 9;268(3):191-7. doi: 10.1016/j.tox.2009.12.015. Epub 2009 Dec 21.
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.
已经广泛认识到一氧化氮（NO）可以抑制内皮细胞的氧化损伤，但对于其在 9,10-菲醌（9,10-PQ）诱导的细胞凋亡中的病理生理作用知之甚少，9,10-PQ 是柴油机废气颗粒中的主要醌类成分。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 引发的凋亡信号转导的每个步骤中的作用。用 9,10-PQ 处理会引发 NO 的钟形产生，这可能是由于内皮型一氧化氮合酶的活性形式增加所致。用外源性 NO 预处理可降低细胞对 9,10-PQ 的敏感性，并从暴露于高浓度 9,10-PQ 时诱导的凋亡信号（活性氧生成、谷胱甘肽耗竭和半胱天冬酶激活）中恢复。此外，内源性 NO 产生的抑制增强了 9,10-PQ 的毒性。有趣的是，9,10-PQ 处理导致蛋白酶体活性明显降低，而 NO 和一种可渗透细胞的 cGMP 类似物可部分阻断这种降低。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 诱导的凋亡信号转导，NO 通过 cGMP 依赖性途径改善了这种信号转导，从而表明 NO 在由 9,10-PQ 引起的血管损伤中的保护作用。
