Date of Award

Fall 1994

Project Type

Dissertation

Program or Major

Animal and Nutritional Sciences

Degree Name

Doctor of Philosophy

First Advisor

Thomas Foxall

Abstract

Estrogens may protect against coronary artery disease (CAD) as women have less CAD than age-matched men, and postmenopausal women on estrogen have less CAD than those without replacement therapy. To elucidate potential benefits of 17 beta-estradiol on atherogenesis, female swine and hamsters were treated to yield three groups: (1) ovariectomized (ovex), (2) ovariectomized with estradiol replacement (ovex + estradiol), and (3) sexually intact. Postoperatively, animals were switched from a low fat to a high fat diet for measurement of acute estradiol effects in swine and chronic effects in hamsters. Swine monocyte and platelet adhesion to porcine aortic endothelial cells (PAEC) were measured as well as mononuclear cell degradation of low density lipoprotein (LDL) during the low fat diet and after 4, 8, and 12 weeks of high fat feeding. Antioxidant content, fatty acid composition, and resistance to oxidation of swine LDL were measured after 14 weeks of experimental diet. In hamsters, aortic lesion area was assessed histologically and ultrastructurally after 4, 9, and 18 months of hormonal treatment. Both animal models became hyperlipidemic on high fat diets. Estradiol did not significantly alter circulating lipid levels. Monocyte adhesion to PAEC was elevated only at 4 weeks of high fat feeding in the ovex + estradiol group while platelet adhesion was unaltered throughout the study. Mononuclear cell degradation of LDL was primarily receptor-mediated and not associated with plasma estradiol levels. Estradiol increased resistance of LDL to oxidation by increasing lag time and decreasing conjugated diene propagation rate. Oxidative resistance was associated with conservation of alpha-tocopherol in LDL from animals with estradiol. Hamster aortic lesion area was less in ovex + estradiol than in ovex animals, although statistically significant only at 4 months of high fat feeding. Lesions were primarily lipid-enriched with no involvement of smooth muscle cells. Older animals, independent of estradiol status, developed lesions characterized by extracellular matrix proliferation punctuated by lipid. Although all animals became hyperlipidemic, total cholesterol to high density cholesterol ratios were approximately 2.0 in all treatment groups throughout the study. Estradiol directly or indirectly altered some of the determinants of atherogenesis potentially reducing the risk for CAD.

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