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

我们的研究目的是阐明雌激素的动脉粥样硬化保护作用，特别是雌激素受体（ER）亚型的作用，并应用雌激素受体预防动脉粥样硬化的新治疗方法。我们在三年中取得了六项成果，如下所述。(1)我们发现低剂量雌激素可抑制大鼠颈动脉球囊损伤后新内膜的形成。这种抑制作用与血管紧张素II型1受体阻滞剂坎地沙坦相当。(2)通过腺病毒介导的ERα和β的过表达，研究了雌激素对血管平滑肌细胞增殖的抑制作用与哪一种ER亚型有关。我们发现雌激素的抑制作用主要是通过下调细胞周期蛋白a介导的ERβ。(3)我们发现雌激素通过ERα和ERβ抑制心脏成纤维细胞的增殖。(4)通过微阵列分析，我们发现了四个基因（caveolin-1、enigma、SmLIM和Id3a），它们在激素替代治疗后在主动脉介质中高表达。(5)血管内皮细胞的凋亡可能与动脉粥样硬化病变的发生有关。我们发现雌激素和雷洛昔芬可以减轻过氧化氢诱导的内皮细胞凋亡。这种作用部分是通过下调Bax表达介导的。(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在中枢神经系统中表达ERβ。(7)成功构建了过表达ER突变体的转基因小鼠，该突变体对ERα和ERβ均具有显性负转录活性。在这只小鼠的股动脉周围放置聚乙烯袖套形成新生内膜。通过这种方法，我们能够明确ER的生物物理效应。(8)我们发现使用一半普通剂量雌激素的激素替代疗法改善了绝经后女性患者的血流依赖性血管舒张反应，并抑制了颈动脉内膜-中膜增厚的进展。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