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ANTIOXIDANT POTENTIAL OF ESTROGENS IN MENOPAUSE

雌激素在更年期的抗氧化潜力

基本信息

批准号：
2519384
负责人：
RAVI MT SUBBIAH
金额：
$ 18.81万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 1999-08-31
项目状态：
已结题

项目摘要

Cardiovascular disease is the leading cause of death in postmenopausal women accounting for approximately 500,000 deaths per year in the United States. Estrogen administration results in a 50% reduction in cardiovascular disease morbidity and mortality. Current evidence suggests that the majority of the cardioprotective effect of estrogens is mediated through mechanisms not involving changes in levels of circulating lipoproteins. As estrogens are putative antioxidants, and as peroxidation of lipoproteins is now believed to play a key role in atherogenesis, an effect of estrogens on plasma lipoprotein peroxidation in women is of potential importance in understanding the mechanism of estrogen action with regard to heart disease. Furthermore, in post menopausal women, especially with diabetes, the lipoprotein could be in a state more conducive to peroxidation. In this proposal we will determine: 1. The effect of exogenous estrogen administration to postmenopausal diabetic and normal control women on metal/H2O2 catalyzed plasma lipoprotein peroxidation potential as measured by the formation of oxysterols and fatty acid oxidation products; 2. The rate of oxidation of LDL isolated from women treated with estrogens by endothelial cells in culture in terms of oxysterol and malonaldehyde formation; 3. The effect of LDL isolated from women treated with estrogens on cholesterol esterification by macrophages, as measured by 14C oleic acid incorporation; 4. The mechanism of antioxidant effect of estrogen on LDL peroxidation. These studies are aimed to establish: (a) whether estrogen(s) has direct effect on the formation of reactive oxygen species by endothelial cells and macrophages in vitro; or (b) whether it preserves endogenous content of antioxidants (vitamine E, C, beta-carotene) within the LDL molecule during oxidation in vitro; (c) whether the antioxidant effect of estrogen(s) is related to its incorporation to LDL molecule; and (d) whether estrogen interferes with cholesteryl esterification which is the most important event in lipid accumulation in arterial wall, shown to be induced by oxidized lipoproteins. These studies should provide evidence for antioxidant protection as one of the mechanisms by which estrogens may decrease the risk of cardiovascular disease in postmenopausal women.

心血管疾病是绝经后妇女死亡的主要原因在美国，每年约有500 000名妇女死亡， States.雌激素给药导致50%的减少，心血管疾病发病率和死亡率。目前的证据表明雌激素的大部分心脏保护作用是通过通过不涉及循环水平变化的机制脂蛋白由于雌激素是公认的抗氧化剂，现在认为脂蛋白在动脉粥样硬化形成中起关键作用，雌激素对女性血浆脂蛋白过氧化作用的影响对于了解雌激素作用机制的潜在重要性关于心脏病。此外，在绝经后妇女中，尤其是糖尿病患者，脂蛋白可能处于一种有利于过氧化作用。在本提案中，我们将确定： 1.外源性雌激素对绝经后妇女的影响糖尿病和正常对照妇女对金属/H2 O2催化的血浆脂蛋白过氧化电位，通过形成氧化固醇和脂肪酸氧化产物; 2.从接受雌激素治疗的妇女中分离的LDL氧化速率通过培养的内皮细胞在氧化固醇和丙二醛方面形成; 3.从雌激素治疗的妇女中分离的LDL对通过14 C油酸测量的巨噬细胞胆固醇酯化成立公司; 4.雌激素对LDL过氧化的抗氧化作用机制。这些研究旨在确定：（a）雌激素是否具有直接的对内皮细胞产生活性氧的影响和巨噬细胞;或（B）其是否保留内源性内容物低密度脂蛋白分子中的抗氧化剂（维生素E，C，β-胡萝卜素）在体外氧化过程中;（c）是否抗氧化效果的雌激素与其与LDL分子的结合有关;和雌激素是否会干扰胆固醇的酯化，动脉壁脂质积聚的最重要事件，显示为由氧化脂蛋白引起。这些研究应该为抗氧化保护提供证据，雌激素可能降低心血管疾病风险的机制绝经后妇女的疾病。