Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress
Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress
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DOI：
10.1161/01.hyp.0000157409.88971.fc
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发表时间：
2005-04-01
期刊：
影响因子：
8.3
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Tsuda, M;Iwai, M;Horiuchi, M
本研究探讨了雌激素增强血管紧张素II 1型（AT（1））受体阻滞剂（ARB）奥美沙坦对动脉粥样硬化的抑制作用的可能性，重点是使用载脂蛋白E基因敲除小鼠（ApoEKO）的氧化应激。高胆固醇饮食6周后，在雄性和雌性ApoEKO小鼠的近端主动脉中观察到明显的动脉粥样硬化病变形成，伴随氧化应激的增加，如超氧化物产生、NAD（P）H氧化酶活性以及p47（phox）mRNA和rac-1 mRNA的表达，而这些变化在雌性小鼠中不太明显。卵巢切除术增强了这些参数，其变化被17 β-雌二醇（80 μ g/kg/天）替代逆转。奥美沙坦（3 mg/kg/天）治疗显著抑制氧化应激和动脉粥样硬化，而其抑制作用在雌性小鼠中比雄性小鼠或卵巢切除小鼠中更显著。较小剂量的奥美沙坦（0.5 mg/kg/天）或17 β-雌二醇（20 μ g/kg/天）不影响卵巢切除小鼠的动脉粥样硬化和氧化应激，而这些剂量的奥美沙坦和17 β-雌二醇联合给药可减弱这些参数。血管紧张素转换酶（ACE）抑制剂，替莫普利，也抑制动脉粥样硬化的变化类似于奥美沙坦。此外，血管紧张素II介导的NAD（P）H氧化酶在培养的血管平滑肌细胞中的激活被17 β-雌二醇减弱。这些结果表明，雌激素和ARB协同减弱动脉粥样硬化至少部分通过抑制氧化应激。
The present study explored the possibility that estrogen enhances the inhibitory effect of an angiotensin II type-1 (AT(1)) receptor blocker (ARB), olmesartan, on atherosclerosis, focusing on oxidative stress using apolipoprotein E knockout mice (ApoEKO). After 6 weeks on a high-cholesterol diet, marked atherosclerotic lesion formation with an increase in oxidative stress, such as superoxide production, NAD(P)H oxidase activity and expression of p47(phox) mRNA and rac-1 mRNA, were observed in the proximal aorta in both male and female ApoEKO mice, whereas these changes were less marked in female mice. Ovariectomy enhanced these parameters, the changes of which were reversed by 17 beta-estradiol (80 mu g/kg per day) replacement. Treatment with olmesartan (3 mg/kg per day) significantly inhibited oxidative stress and atherosclerosis, whereas its inhibitory effects were more marked in female than in male or ovariectomized mice. Smaller doses of olmesartan (0.5 mg/kg per day) or 17 beta-estradiol (20 mu g/kg per day) did not influence atherosclerosis and oxidative stress in ovariectomized mice, whereas co-administration of olmesartan and 17 beta-estradiol at these doses attenuated these parameters. An angiotensin-converting enzyme (ACE) inhibitor, temocapril, also inhibited atherosclerotic changes similarly to olmesartan. Moreover, angiotensin II-mediated activation of NAD( P) H oxidase in cultured vascular smooth muscle cells was attenuated by 17 beta-estradiol. These results indicate that estrogen and an ARB synergistically attenuate atherosclerosis at least partly via inhibition of oxidative stress.