Investigation and clinical application 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 examined the influence of diabetes mellitus on atherosclerosis in relation to ER. We showed that the expression of Erα was decreased in high glucose state in cultured vascular smooth muscle cells, mediated through the activation of protein kinase C. (2) 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. (3) We examined which ER subtype was involved in the inhibitory effect of estrogen on vascular smooth muscle cell proliferation using adenovirus-mediated overexpression of Erα and β. We found that the inhibitory effect was mediated mainly via Erβ. (4) Apoptosis of vascular endothelium is supposed to be related to the initiation of atherosclerotic lesion. We showed that estrogen attenuated apoptosis of endothelium. This effect was mediated, in part, through the downregulation of Bax expression. (5) 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. (6) We investigated the association between the polymorphism of CA (cytosine-adenine) repeat in the upstream of Erβ gene and blood pressure in 187 Japanese postmenopausal women. We found that a group of subjects who bears a specific CA repeats showed significant systolic hypertension.