|Corcoran, Michael P. -|
|Lichtenstein, Alice H. -|
|Meydani, Mohsen -|
|Dillard, Alice -|
|Schaefer, Ernst J. -|
|Lamon-Fava, Stefania -|
Submitted to: Journal of Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 1, 2011
Publication Date: August 3, 2011
Citation: Corcoran, M., Lichtenstein, A., Meydani, M., Dillard, A., Schaefer, E., Lamon-Fava, S. 2011. The effect of 17 beta-estradiol on cholesterol in human macrophages is influenced by the lipoprotein milieu. Journal of Molecular Endocrinology. 47(1):109-117. Interpretive Summary: Heart disease is caused by the formation of plaques in the coronary arteries, which supply the heart muscle with oxygenated blood. The most important cell in plaques is the macrophage, which is involved both in the accumulation of cholesterol and in the local inflammatory reaction that accompanies the plaque formation. It has long been known that women tend to develop heart disease on average 10 year later than men, and thus it is thought that the female sex hormone estrogen and the male sex hormone testosterone may modulate the function of macrophages. In our study, macrophages obtained from 10 healthy older men and 10 postmenopausal women were cultured in vitro in the presence of estrogen or testosterone. We found that treatment of macrophages with estrogen, but not testosterone, was associated with a significant reduction in cell cholesterol content. In similar experiments conducted in an established macrophage cell line THP-1, the reduction in cholesterol content by estrogen was mediated by the estrogen receptor. In addition, in THP-1 cells, the reduction in cholesterol accumulation was greater in cells not exposed to oxidized lipoproteins, than in cells exposed to oxidized lipoprotein. These results indicate that estrogen may reduce the accumulation of cholesterol in macrophages, but that a pro-atherogenic lipoprotein milieu, as observed in older women with cardiovascular disease, may lead to a reduction in this beneficial effect of estrogen.
Technical Abstract: Estrogen and testosterone are thought to modulate coronary heart disease (CHD) risk. To examine how these hormones affect human macrophage cholesterol transport, a key factor in atherogenesis, we obtained monocytes from healthy male and postmenopausal female donors (age 50-70 y). Cells were allowed to differentiate in autologous serum. Human monocyte-derived macrophages (HMDMs) were exposed to estrogen, testosterone, or vehicle, during differentiation. Cells were cholesterol-enriched with oxidized LDL (oxLDL) in the presence of treatment. Cell cholesterol mass, efflux, and the expression of proteins involved in HMDM cholesterol transport were examined. Estrogen significantly reduced cholesteryl ester content in both female and male HMDMs while having no measurable effect on cholesterol efflux. Testosterone did not affect cholesterol content or efflux. Both hormones significantly but modestly affected the gene expression of several proteins involved in HMDM transport, yet these effects did not translate into significant changes in protein expression. In THP-1 macrophages, the effect of estrogen on cholesteryl ester content was more potent in unloaded macrophages and was estrogen receptor-dependent. A trend for a reduction in non-oxidized LDL uptake by estrogen was observed and was also found to be dependent upon ER activation. Our data indicate that estrogen, but not testosterone, reduces cholesteryl ester accumulation in HMDMs obtained from a CHD-age relevant population, independent of changes in the expression of proteins important to macrophage cholesterol transport. In THP-1 cells, this effect is reduced in the presence of oxLDL indicating that a pro-atherogenic lipoprotein milieu is an important variable in sex hormone modulation of CHD.