| Objective: A preponderance of epidemiological studies have demonstrated striking gender differences in the prevalence of cardiovascular disease. One reason for this discrepancy is that women exhibit significantly less risk of developing cardiovascular disease during their child-bearing years compared to men of similar age , however, a woman's protection against cardiovascular dysfunction is gradually lose after menopause, cessation of ovarian function after natural or surgical menopause increases the risk of atherosclerosis, and with increasing age, the incidence of coronary artery disease is thought to become similar in men and women. Moreover, 17β-0estradiol is effective for secondary prevention of experimental atherosclerosis. Several retrospective, large-scale epidemiological studies have suggested that hormone replacement therapy (HRT) might lower cardiovascular morbidity and mortality. The estrogen protection hypothesis became familiar, almost axiomatic, but the pathways by which estrogens interact with the cardiovascular physiology are not completely understood. Estrogens lower plasma lipoproteins, modulate vascular smooth muscle and endothelial cell function, blood pressure, vascular growth, inflammation, coagulation and fibrinolysis, influence the renin-angiotension system, exert antioxidative properties, and may act as calcium blocking agents. Estrogens have sustained "genomic" action that involve activation of nuclear receptors, as well as "non-genomic" functions. However, the Heart and Estrogen/progestin Replacement study (HERS) and the Estrogen Replacement and Atherosclerosis study (ERA) found no effect of HRT over the three and four year treatment periods, respectively on disease progression or cardiovascular mortality. This surprising outcome in HERS and ERA has been attributed to the addition of progesterone, a relatively 'toxic'synthetic progestin that inhibits beneficial vascular effects of estrogen in vitro and in vivo. Progesterone could display a number of potential adverse effects on the cardiovascular system that might overcome the beneficial influence of estrogens. In this context, reduction of HDL levels, down-regulation of estrogen receptors, decreased carbohydrate tolerance, and reduced blood flow and vasodilatation have been reported. In any event, the molecular mechanisms by which a concomitant progesterone therapy could counteract the estrogen replacement treatment are not known in detail and are the subject of controversy, because some study results could not support the deleterious effects of Progesterone. The AT1 receptor mediates many biological effects of the renin-angiotensin system (RAS), such as vasoconstriction, water and sodium retention, free radical release, and cell growth. Therefore, activation of the AT1 receptor has been implicated in the pathogenesis of cardiovascular disease . We hypothesized that potentially counteracting effects of estrogens and progestins on the cardiovascular system could take place at the level of AT1 receptor regulation, To further investigate the direct effects of these reproductive hormones on vascular cells, we examined their influence on AT1 receptor mRNA expression in vascular smooth muscle cells (VSMCs) and sought to clarify the underlying molecular mechanisms. Methods and Results: 1 Time dependency of effect of 17β-estradiol and progesterone on expression of AT1RmRNA in VSMCs.co-incubation of SMCs and 17β-estradiol, progesterone were performed to evaluate the direct effect of estradiol and progesterone on the cultured SMCs. The experiments were divided into five groups. Cells were incubated for 0, 2, 4,12,24hours with 0.1nM either 17β-estradiol or progesterone. After incubation, the cells were washed with PBS twice,then were removed by trypsin-EDTA digestion and were collected by centrifugation. Cells were then prepared for total mRNA extraction. AT1RmRNA was measured by RT-PCR. The results showed that 17β-estradiol caused a significant decrease of AT1RmRNA after 2 hours, reaching the maximum...
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