NADPH Oxidase Isoforms and Anti-hypertensive Effects of Atorvastatin Demonstrated in Two Animal Models
NADPH Oxidase Isoforms and Anti-hypertensive Effects of Atorvastatin Demonstrated in Two Animal Models
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DOI：
10.1254/jphs.09148fp
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Yabe-Nishimura, Chihiro
中科院分区：
文献类型：
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作者：
Cui, Wenhao;Matsuno, Kuniharu;Yabe-Nishimura, Chihiro
他汀类药物对心血管疾病的有益作用归因于减少活性氧（ROS）的产生。我们在两种高血压动物模型中验证了阿托伐他汀通过降低NADPH氧化酶衍生的ROS水平来预防高血压发展的假设。阿托伐他汀被给予长期输注血管紧张素（Ang）II的小鼠或高脂饮食喂养的载脂蛋白E（ApoE）缺陷小鼠。阿托伐他汀显著抑制了两种动物模型中的平均血压（MBP）升高，并降低了主动脉中的ROS生成。阿托伐他汀治疗没有改变NOX 1（NADPH氧化酶的催化亚基）的mRNA水平，但降低了喂食高脂饮食的ApoE缺陷小鼠中其他NOX亚型NOX 2和NOX 4的水平。在用他汀类药物治疗的Ang II灌注模型中，仅NOX4 mRNA水平降低。血管紧张素II输注小鼠经阿托伐他汀治疗后，Rac 1的膜转位显著减少。最后，阿托伐他汀给药缺乏Nox1基因的Ang II输注小鼠引起额外的下降，MBP与Nox1缺陷小鼠治疗的车辆。总之，这些发现表明，NADPH氧化酶亚型（涉及NOX 1、NOX 2，可能还有NOX 4）的表达和活性降低介导了阿托伐他汀的抗高血压作用。
Beneficial effects of statins on cardiovascular diseases have been attributed to decreased generation of reactive oxygen species (ROS). We tested the hypothesis that atorvastatin protects against the development of hypertension by reducing levels of NADPH oxidase-derived ROS in two hypertensive animal models. Atorvastatin was given to mice chronically infused with angiotensin (Ang) II or to apolipoprotein E (ApoE)-deficient mice fed a high-fat diet. Increased mean blood pressure (MBP) demonstrated in both animal models was significantly suppressed by atorvastatin with reduced ROS production in the aorta. Treatment with atorvastatin did not alter the mRNA level of NOX1, a catalytic subunit of NADPH oxidase, but decreased the levels of other NOX isoforms, NOX2 and NOX4, in the ApoE-deficient mice fed a high-fat diet. In the Ang II-infused model treated with statin, only the NOX4 mRNA level was reduced. Membrane translocation of Rac1 was significantly reduced in the Ang II-infused mice treated with atorvastatin. Finally, atorvastatin administered to Ang II-infused mice lacking the Nox1 gene elicited an additional decline in MBP compared to Nox1-deficient mice treated with vehicle. Together, these findings suggest that reduced expression and activity of the isoforms of NADPH oxidase, involving NOX1, NOX2, and possibly NOX4, mediate the anti-hypertensive effect of atorvastatin.