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.
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