Tokoro Takashi, Wang Juyong, Kitajima Isao
Clinical Laboratory Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Yakugaku Zasshi. 2004 Mar;124(3):121-6. doi: 10.1248/yakushi.124.121.
This study sought to induce the effect of nitric oxide (NO) production in vascular endothelial cells by Pitavastatin, which is a novel HMG-CoA reductase inhibitor (statin). The growth capacity of vascular endothelial cells significantly (p < 0.01) declined when stimulated with TNF-alpha (10 ng/ml). The growth capacity of the TNF-alpha treated cells recovered, when the TNF-alpha stimulation was performed after Pitavastatin (100 nM) pretreatment. The recovery of the growth capacity of the cells was suppressed by the presence of the NO synthase inhibitor, L-NAME. Pitavastatin increased NO production by the vascular endothelial cells in a dose and time dependent manner. The NO production was suppressed by the presence of mevalonic acid and geranylgeranyl pyrophosphate. In addition, the expression of endothelial nitric oxide synthase was strongly induced by Pitavastatin, and was suppressed by mevalonic acid and geranylgeranyl pyrophosphate by Western blot analysis. Our results show that Pitavastatin induces NO production by vascular endothelial cells, and protects vascular endothelial cells from injury due to the inflammatory reaction induced by TNF-alpha.
本研究旨在探讨新型HMG-CoA还原酶抑制剂（他汀类药物）匹伐他汀对血管内皮细胞一氧化氮（NO）生成的影响。用肿瘤坏死因子-α（TNF-α，10 ng/ml）刺激时，血管内皮细胞的生长能力显著下降（p < 0.01）。在匹伐他汀（100 nM）预处理后再进行TNF-α刺激，经TNF-α处理的细胞的生长能力得以恢复。一氧化氮合酶抑制剂L-NAME的存在抑制了细胞生长能力的恢复。匹伐他汀以剂量和时间依赖性方式增加血管内皮细胞的NO生成。甲羟戊酸和香叶基香叶基焦磷酸的存在抑制了NO的生成。此外，通过蛋白质印迹分析发现，匹伐他汀强烈诱导内皮型一氧化氮合酶的表达，而甲羟戊酸和香叶基香叶基焦磷酸则抑制其表达。我们的结果表明，匹伐他汀可诱导血管内皮细胞生成NO，并保护血管内皮细胞免受TNF-α诱导的炎症反应所致的损伤。
