Regression of Atherosclerosis by Amlodipine via Anti-Inflammatory and Anti-Oxidative Stress Actions
Regression of Atherosclerosis by Amlodipine via Anti-Inflammatory and Anti-Oxidative Stress Actions
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DOI：
10.1291/hypres.29.457
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发表时间：
2006-06-01
影响因子：
5.4
通讯作者：
Horiuchi, Masatsugu
中科院分区：
文献类型：
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作者：
Yoshii, Toyofumi;Iwai, Masaru;Horiuchi, Masatsugu
我们研究了L类钙通道阻滞剂阿米地平是否对载脂蛋白E缺陷小鼠的氧化应激和炎症反应有抑制作用，从而抑制动脉粥样硬化。成年雄性ApoEKO小鼠(6周龄)给予高胆固醇饮食(HCD)8或10周，同时或不给予氨氯地平(3 mg/kg/d)10周或仅HCD的最后2周。HCD灌胃后，观察近端动脉粥样硬化病变的形成、超氧化物歧化产物的原位生成和NADPH氧化酶活性。免疫组织化学和实时定量逆转录聚合酶链式反应检测NADPH氧化酶亚基(P47(Phox)和RAC-1)、单核细胞趋化蛋白-1(MCP-1)、细胞间黏附分子-1(ICAM-1)和血管细胞黏附分子-1(VCAM-1)的表达。给ApoEKO小鼠注射HCD 8-10周后，观察到近端动脉形成明显的动脉粥样硬化病变。在动脉粥样硬化病变中，超氧化物歧化产物、NADPH氧化酶亚基的表达和NADPH氧化酶活性增加，MCP-1、ICAM-1和VCAM-1的表达增加。在服用氨氯地平同时服用HCD 10周的小鼠中，这些变化被抑制，而血压和血浆胆固醇水平没有显著变化。我们还观察到，仅在最后两周使用氨氯地平治疗可使动脉粥样硬化病变消退，氧化应激和血管炎症减少。氨氯地平抑制主动脉近端动脉粥样硬化病变面积和脂质面积的作用与其对氧化应激、炎症和黏附分子产生的抑制作用有关。这些结果表明，氨氯地平不仅可以抑制动脉粥样硬化病变的形成，而且还可以逆转动脉粥样硬化，这些作用至少部分是由于抑制了氧化应激和炎症反应。(Hyperten Res 2006；29：457-466)
We examined whether amiodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. We also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response. (Hypertens Res 2006; 29: 457-466)