17B ESTRADIOL EFFECTS ON ENDOTHELIAL CELL FUNCTION

17B 雌二醇对内皮细胞功能的影响

基本信息

批准号：
6056073
负责人：
TERESA L CAULIN-GLASER
金额：
$ 12.07万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-01 至 2001-08-31
项目状态：
已结题

项目摘要

The proposal is aimed at continuing to investigate the theory that estrogen (E2) is involved in protection against atherosclerosis. Epidemiological studies have supported the fact that E2 replacement provides a protective effect against coronary disease. After menopause the risk of myocardial Infarction increases and the incidence approaches equal to that of males after the age of 55, E2 replacement results in a 50% reduction in cardiovascular and cerebrovascular mortality relative to women who do not receive therapy. The hypothesis is that E2 via the endothelial cell(EC) E2 receptor(ER) is effecting EC function resulting in inhibition of cytokine-mediated endothelial cell adhesion molecules(CAM) thereby decreasing the adhesive state of the endothelium in inflammation; augmentation of basal nitric oxide synthase (NOS) activity which results in vasomotor stability enhancement and inhibition of leukocyte adhesion to the endothelium. Based on preliminary data further studies will be elucidating the cis-acting elements in the CAM promotors which E2 interacts using a transfection model; determining if E2 regulation of genes for CAM is by interaction of the ER complex with nuclear E2 response elements or by regulation of other gene products; studying the effects of E2 on NOS at the mRNA, protein and NO production level. The study of the cellular and molecular effects of E2 on EC function is a vital component to understanding the vasculoprotective effects of ovarian hormones and the future Implications for a therapeutic role of the hormones in cardiovascular disease.

该提案旨在继续研究以下理论：雌激素（E2）参与预防动脉粥样硬化。流行病学研究支持 E2 替代疗法这一事实提供针对冠状动脉疾病的保护作用。绝经后心肌梗死的风险增加且发病率接近与 55 岁以后的男性相比，E2 替代效果提高了 50% 心脑血管死亡率相对于未接受治疗的女性。假设 E2 通过内皮细胞 (EC) E2 受体 (ER) 影响 EC 功能，导致抑制细胞因子介导的内皮细胞粘附分子（CAM）从而降低炎症中内皮的粘附状态；基础一氧化氮合酶（NOS）活性增强增强血管舒缩稳定性和抑制白细胞粘附内皮细胞。根据初步数据，将进一步研究阐明 CAM 启动子中的顺式作用元件，其中 E2 使用转染模型相互作用；确定 E2 调节是否 CAM 基因通过 ER 复合物与核 E2 反应相互作用元素或通过其他基因产物的调节；研究的影响 E2 在 mRNA、蛋白质和 NO 产生水平上作用于 NOS。该研究的 E2 对 EC 功能的细胞和分子影响是重要组成部分了解卵巢激素的血管保护作用和激素治疗作用的未来意义心血管疾病。