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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL050881-01
Application #
3369811
Study Section
Special Emphasis Panel (ZHL1-CSR-C (S1))
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Subbiah, M T R (2002) Estrogen replacement therapy and cardioprotection: mechanisms and controversies. Braz J Med Biol Res 35:271-6
Subbiah, M T Ravi; Abplanalp, William (2002) Evidence of increased formation of products retaining strong antioxidant activity from estradiol-17beta oxidation in the presence of human plasma lipoproteins. J Lab Clin Med 139:357-63
Scheiber, M D; Liu, J H; Subbiah, M T et al. (2001) Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause 8:384-92
Abplanalp, W; Ravi Subbiah, M T (2001) Uptake and protection against oxidative stress by estrogen esters in THP-1 human macrophage cell lines. Gynecol Obstet Invest 51:81-4
Abplanalp, W; Scheiber, M D; Moon, K et al. (2000) Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens. Eur J Endocrinol 142:79-83
Abplanalp, W; Rymaszewski, M; Adamski, J et al. (1999) Evidence for interference in estradiol-17beta inactivation to estrone by oxidized low-density lipoprotein and selected lipid peroxidation products. J Lab Clin Med 134:253-9
Ayres, S; Baer, J; Subbiah, M T (1998) Exercised-induced increase in lipid peroxidation parameters in amenorrheic female athletes. Fertil Steril 69:73-7
Ayres, S; Abplanalp, W; Liu, J H et al. (1998) Mechanisms involved in the protective effect of estradiol-17beta on lipid peroxidation and DNA damage. Am J Physiol 274:E1002-8
Subbiah, M T (1998) Mechanisms of cardioprotection by estrogens. Proc Soc Exp Biol Med 217:23-9
Tang, M; Abplanalp, W; Subbiah, M T (1997) Association of estrogens with human plasma lipoproteins: studies using estradiol-17beta and its hydrophobic derivative. J Lab Clin Med 129:447-52

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