It is well established that women are protected from atherosclerosis and coronary heart disease relative to men, and that this protection is lost after menopause. Estrogen replacement restores much of this lost protection. Nonetheless, the mechanisms by which estrogens exert this protection are poorly understood. Changes in plasma lipoproteins can explain only a small part of this protection and a considerable body of data points to a direct effect of estrogens on the arterial wall. Although the mechanism by which estrogens protect against development of atherosclerosis at the level of the arterial wall is unknown, studies with non human primates and rabbits and preliminary data from macrophages in culture, suggest a direct effect of estrogens on macrophages that reduces cholesterol accumulation and ultimately foam cell formation. The purpose of the proposed studies is to define the cellular mechanism(s) by which estrogens modify the excessive accumulation of cholesterol in macrophages leading to reduced foam cell development. The studies will utilize the human THP-1 macrophage cell line and human monocyte macrophages.
Specific aim 1 will determine the effect of 17b-estradiol and other estrogens and steroids on metabolism of lipoproteins (LDL, VLDL, beta-VLDL, oxidized LDL, aggregated LDL), thought to be present in the arterial wall, and on intracellular cholesterol balance, with a focus on enzymes responsible for cholesteryl ester synthesis, hydrolysis and cholesterol efflux.
Specific aim 2 will address estrogen modulation of cell surface proteoglycan synthesis, metabolism and structure and subsequent effects on lipoprotein uptake and cholesterol accumulation mediated by cell surface proteoglycans. The role of estrogens on the synthesis and secretion of potential modulators of lipoprotein proteoglycan interactions, such as lipoprotein lipase and apo E, also will be studied. These investigators believe that these studies represent one of the first comprehensive investigations of the role of estrogens on macrophage foam cell development. As a result, important new information on one of the potential mechanisms by which estrogens may reduce atherosclerosis at the level of the arterial wall could be forthcoming.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pathology A Study Section (PTHA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Lada, Aaron T; Rudel, Lawrence L; St Clair, Richard W (2003) Effects of LDL enriched with different dietary fatty acids on cholesteryl ester accumulation and turnover in THP-1 macrophages. J Lipid Res 44:770-9
Ghosh, Shobha; St Clair, Richard W; Rudel, Lawrence L (2003) Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase. J Lipid Res 44:1833-40
Lada, Aaron T; Willingham, Mark C; St Clair, Richard W (2002) Triglyceride depletion in THP-1 cells alters cholesteryl ester physical state and cholesterol efflux. J Lipid Res 43:618-28
Mikkola, Tomi S; St Clair, Richard W (2002) Estradiol reduces basal and cytokine induced monocyte adhesion to endothelial cells. Maturitas 41:313-9