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对动脉粥样硬化的保护作用，特别是雌激素受体(ER)亚型的作用，为雌激素预防动脉粥样硬化提供新的治疗方法。我们在这三年中取得了六项成果，如下所述。(1)我们发现小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)用腺病毒介导的ERα和β过表达检测ER亚型参与雌激素抑制血管平滑肌细胞增殖的作用。我们发现雌激素对心脏成纤维细胞的抑制作用主要是通过下调细胞周期蛋白A的β来实现的。(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)通过基因芯片分析，我们鉴定了4个高表达…的基因(小窝蛋白-1、谜、SmLIM和id3a)。对激素替代治疗的反应更多地发生在主动脉中膜。(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减轻过氧化氢诱导的内皮细胞凋亡。这种作用在一定程度上是通过下调Bax的表达来实现的。(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。我们发现雌激素抑制作用的机制是通过中枢神经系统表达ERβ来实现的。(7)成功构建了对ERα和ERβ均具有显性负转录活性的高表达突变体ER转基因小鼠。这只小鼠的新生内膜是通过在股动脉周围放置聚乙烯套形成的。通过这种方法，我们能够阐明内质网的生物物理效应。(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扩张反应，并抑制了颈动脉内膜-中层增厚的进展。较少

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