埼玉医科大学雑誌 第32巻 第1号 (2005年1月) 1-11頁 ◇論文(図表を含む全文)は，PDFファイルとなっています．
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Mechanism of Inhibitory Action of AT1 Receptor Blocker and Estrogen on Atherosclerosis
Masahiro Tsuda (Department of Nephrology, Saitama Medical School, Moroyama, Iruma-gun, Saitama, 350-0495, Japan)
In the present study, we investigated a gender difference of atherosclerotic changes induced in apoE-deficient (ApoEKO)mice, focusing on oxidative stress, and the possible interaction between olmesartan, an AT1 (angiotensin type 1 receptor)blocker(ARB), and estrogen. After treatment with high cholesterol diet(HCD) for 6 weeks, apparent atherosclerotic lesion formation including lipid deposition and increase in superoxide production and p47phox expression were observed in ApoEKO mice. These changes were significantly greater in male than in female mice, although plasma cholesterol level was not different. Preceding ovariectomy enhanced atherosclerotic lesion and oxidative stress 6 weeks after HCD. The changes in ovariectomized mice were reversed by 17β-estradiol(80μg/kg/day)replacement. On the other hand, olmesartan(3 mg/kg/day)inhibited both atherosclerosis and oxidative stress observed in ApoEKO mice treated with HCD. The inhibitory effect of olmesartan on atherosclerosis was significantly stronger in female than in male and ovariectomized ApoEKO mice. Neither the smaller dose of estrogen(20μg/kg/day)nor olmesartan(0.5 mg/kg/day)influenced atherosclerosis and oxidative stress. However, co-administration of olmesartan and estrogen at these smaller doses attenuated atherosclerosis as well as oxidative stress. We further investigated interaction between AT1 receptor stimulation and estrogen on NADPH oxidase activity using cultured VSMC, which mainly was expressed AT1 receptor. The NADPH oxidase activity in cultured VSMC was increased by Angiotensin II. 17β-estradiol attenuated NADPH oxidase activity induced by angiotensin II without affecting the expression of AT1 receptor. These results indicate that estrogen enhances the inhibitory effect of AT1 receptor blocker on atherosclerosis. Our results also suggest that estrogen and ARB act synergistically to inhibit oxidative stress, by attenuating NADPH oxidase activity.