Investigation and clinical application to the prevention of estrogen receptor α and β prevent vascular disease.

本研究的目的是阐明雌激素的抗动脉粥样硬化作用，特别是雌激素受体（ER）亚型的作用，并应用ER预防动脉粥样硬化的新的治疗方法。三年来，我们取得了以下六项成果。(1)我们发现低剂量雌激素抑制大鼠颈动脉球囊损伤后新生内膜的形成。这种抑制作用与血管紧张素II 1型受体阻滞剂坎地沙坦相当。(2)我们利用腺病毒介导的ERα和ER β过表达来检测哪种ER亚型参与雌激素对血管平滑肌细胞增殖的抑制作用。我们发现，ERβ主要通过下调cyclin A的表达而介导其抗肿瘤作用。(3)我们观察到雌激素通过ERα和ERβ抑制心脏成纤维细胞的增殖。(4)利用微阵列分析，我们鉴定了4个基因（小窝蛋白-1，enigma，SmLIM和Id 3a），它们在大肠杆菌中高度表达。 关于我们 激素替代疗法的反应。(5)血管内皮细胞凋亡与动脉粥样硬化病变的发生有关。我们发现，雌激素以及雷洛昔芬衰减过氧化氢诱导的内皮细胞凋亡。这种作用是介导的，部分，通过下调Bax的表达。(6)肥胖是动脉粥样硬化的重要危险因素之一，雌激素具有抗肥胖作用。我们发现雌激素的抑制作用机制是通过中枢神经系统表达的ERβ。(7)我们成功构建了对ERα和ERβ均具有显性负转录活性的突变型ER转基因小鼠。通过将聚乙烯套囊放置在股动脉周围，在该小鼠中形成新生内膜。通过这种方法，我们能够阐明ER的生物物理效应。(8)我们发现，激素替代治疗使用一半的普通剂量的雌激素改善血流依赖性血管舒张反应，抑制颈动脉内膜中层增厚的进展，在绝经后女性患者。少

The goal of our study is to elucidate the atheroprotective effects of estrogen, especially the role of estrogen receptor (ER) subtype, and to apply a new therapeutic method using ER to prevent atherosclerosis. We have gained six results for the three years, described below. (1) We found that low dose of estrogen suppressed neointima formation after balloon-injury in rat carotid arteries. This suppressive effect was comparable to that of angiotensin II type 1 receptor blocker, candesartan. (2) We examined which ER subtype was involved in the inhibitoiy effect of estrogen on vascular smooth muscle cell proliferation using adenovirus-mediated overexpression of ERα and β. We found that the inhibitoiy effect was mediated mainly via ERβ through the downregulation of cyclin A. (3) We observed that estrogen inhibited the proliferation of cardiac fibroblasts via both ERα and ERβ. (4) Using microarray analysis, we identified four genes (caveolin-1, enigma, SmLIM and Id3a), which were highly expr … More essed in aortic media in response to hormone replacement therapy. (5) Apoptosis of vascular endothelium is supposed to be related to the initiation of atherosclerotic lesion. We showed that estrogen as well as raloxifen attenuated endothelial apoptosis induced by hydrogen peroxide. This effect was mediated, in part, through the downregulation of Bax expression. (6) Obesity is one of the important risk factors for atherosclerosis, and estrogen has anti-obese effect. We found that the mechanism of the inhibitory effect of estrogen is through ERβ expressed in the central nervous system. (7) We successfully constructed transgenic mouse overexpressing mutant ER which has a dominant negative transcriptional activity to both ERα and ERβ. Neointima was formed in this mouse by placing polyethylene cuff around the femoral artery. By this method, we were able to clarify the biophysical effect of ER. (8) We found that hormone replacement therapy using half ordinary dose of estrogen improved flow dependent vasodilatory response and suppressed the progression of carotid intima-media thickening in postmenopausal female patients. Less