Cellular Antioxidant Effects of Atorvastatin In Vitro and In Vivo
Cellular Antioxidant Effects of Atorvastatin In Vitro and In Vivo
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DOI：
10.1161/hq0202.104081
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发表时间：
2002-02
期刊：
影响因子：
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通讯作者：
S. Wassmann;U. Laufs;K. Müller;C. Konkol;K. Ahlbory;A. Bäumer;W. Linz;M. Böhm;G. Nickenig
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文献类型：
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作者：
S. Wassmann;U. Laufs;K. Müller;C. Konkol;K. Ahlbory;A. Bäumer;W. Linz;M. Böhm;G. Nickenig
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可能对血管细胞产生直接作用，并有益地影响内皮功能障碍。由于活性氧（ROS）可能导致血管损伤和功能障碍，我们研究了阿托伐他汀对ROS产生的影响及其机制。培养的大鼠主动脉血管平滑肌细胞与10 mol/L阿托伐他汀共同孵育。血管紧张素II诱导和表皮生长因子诱导的活性氧产生显着减少阿托伐他汀（二氯荧光素荧光激光显微镜）。阿托伐他汀下调NAD（P）H氧化酶亚基nox 1的mRNA表达，而p22 phox mRNA表达没有显著改变（逆转录-聚合酶链反应，北方分析）。阿托伐他汀可抑制激活NAD（P）H氧化酶所需的rac 1 GT3的膜易位（Western印迹）。超氧化物歧化酶亚型和谷胱甘肽过氧化物酶的mRNA表达未被阿托伐他汀修饰，而过氧化氢酶的表达在mRNA和蛋白质水平上调，导致酶活性增加。阿托伐他汀对ROS产生和nox 1，rac 1和过氧化氢酶表达的影响被l-甲羟戊酸抑制，但不被25-羟基胆固醇抑制。此外，自发性高血压大鼠用阿托伐他汀治疗30天。在他汀类药物治疗的大鼠中，主动脉节段中的ROS产生显著减少（光泽精化学发光）。阿托伐他汀治疗降低了p22 phox和nox 1的血管mRNA表达，增加了主动脉过氧化氢酶的表达。超氧化物歧化酶、谷胱甘肽过氧化物酶和NAD（P）H氧化酶亚基gp 91 phox、p40 phox、p47 phox和p67 phox的mRNA表达保持不变。在体内，rac 1从细胞质到细胞膜的易位也减少了。因此，阿托伐他汀在培养的大鼠血管平滑肌细胞和自发性高血压大鼠的血管系统中发挥细胞抗氧化作用，通过降低必需NAD（P）H氧化酶亚基的表达和上调过氧化氢酶表达介导。阿托伐他汀的这些作用可能有助于他汀类药物的血管保护作用。
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 mol/L atorvastatin. Angiotensin II–induced and epidermal growth factor–induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription–polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by l-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.