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

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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