Education:
- Undergraduate: Colorado State University, BS, 1962
- Postgraduate: Colorado State University, PhD, 1965
- Fellowship: Bowman Gray School of Medicine, 1965-67
Interests:
- Teaching: Dyslipoproteinemias, Atherosclerosis, Vascular Disease
- Research: Experimental Atherosclerosis in Animal Models (Monkeys, Pigeons, Rabbits), Arterial Wall Lipid and Lipoprotein Metabolism, Lipoprotein Metabolism by Cells in Culture (Macrophages, Smooth Muscle Cells, etc.) Mechanisms of Cellular Cholesterol Efflux, Estrogen and Macrophage Foam Cell Formation
Current Research: Cellular mechanisms in the pathogenesis of atherosclerosis: regulation of macrophage foam cell development and regulation of cellular cholesterol trafficking by hormones
My overall research interests are directed toward the study of factors that influence the progression and regression of atherosclerosis. To accomplish this, studies are being conducted in animal models, including pigeons, rabbits and nonhuman primates, to determine the influence of a variety of dietary factors, hormones and drugs on plasma lipids, lipoproteins and atherosclerosis. A particular focus is on the role of macrophages and macrophage foam cells in the pathogenesis of atherosclerosis. This includes studies on the uptake and metabolism of plasma lipoproteins by the arterial wall, the mechanisms by which normal and abnormal lipoproteins are taken up by macrophages in culture, the effect of the physical state of cholesteryl ester inclusions on their ability to be hydrolyzed and effluxed from macrophages, and the effect of estrogens on monocyte adhesion to the endothelium and development of macrophage foam cells. A particular emphasis is on the rate-limiting steps in the influx and efflux of cellular cholesterol. The role of estrogen receptors in mediating differences in macrophage cholesterol trafficking is being studied using the THP-1 macrophage cell line and human monocyte macrophages in culture using adenoviral vectors for the transient transfection of these cells with different estrogen receptors.
Another major research interest involves the role of arterial wall cells in mediating genetic differences in atherosclerosis susceptibility and resistance. For this, we are using two unique breeds of pigeons that are naturally susceptible (White Carneau, WC) or resistant (Show Racer, SR) to development of atherosclerosis. This difference is genetically mediated since offspring from WC and SR crosses have an intermediate susceptibility to atherosclerosis. This difference is not mediated by traditional risk factors, however, since there are no differences in plasma lipid or lipoprotein concentration or composition, blood pressure, etc. between either breed. The genetic difference in susceptibility most likely is mediated at the level of the arterial wall, and recent bone marrow transplant studies have shown that a major portion of this difference in susceptibility to atherosclerosis can be attributed to the macrophages. Using elicited peritoneal macrophages in culture from WC and SR pigeons, we are studying differences in foam cell formation using a variety of normal and abnormal lipoproteins, cholesterol efflux to a variety of cholesterol acceptors, and susceptibility to apopototic and necrotic cell death.
Figure Legend: Hypothetical temporal sequence of events in the interaction of arterial wall cells [endothelial cells (EC), macrophages (MØ), smooth muscle cells (SMC)] and lipoproteins (LDL, VLDL, HDL) and oxidized LDL (OX-LDL) in the pathogenesis of atherosclerosis.
Recent Publications:
Zhao B, Song J, Chow WN, St Clair RW, Rudel LL, Ghosh S. Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice. J Clin Invest. 2007 Oct;117(10):2983-92.
Zhao B, Song J, St Clair RW, Ghosh S. Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages. Am J Physiol Cell Physiol. 2007 Jan;292(1):C405-12.
Zhao B, Fisher BJ, St Clair RW, Rudel LL, Ghosh S. Redistribution of macrophage cholesteryl ester hydrolase from cytoplasm to lipid droplets upon lipid loading. J Lipid Res. 2005 Oct;46(10):2114-21.
Mikkola TS, Anthony MS, Clarkson TB, St Clair RW. Serum cholesterol efflux potential is an independent predictor of coronary artery atherosclerosis. Atherosclerosis. 2003 Sep;170(1):31-8.
Ghosh S, St Clair RW, Rudel LL. Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase. J Lipid Res. 2003 Oct;44(10):1833-40.
Lada AT, Rudel LL, St Clair RW. Effects of LDL enriched with different dietary fatty acids on cholesteryl ester accumulation and turnover in THP-1 macrophages. J Lipid Res. 2003 Apr;44(4):770-9.
Clarkson TB, Anthony MS, Mikkola TS, St Clair RW. Comparison of tibolone and conjugated equine estrogens effects on carotid artery atherosclerosis of postmenopausal monkeys. Stroke. 2002 Nov;33(11):2700-3.
:Mikkola TS, St Clair RW. Estradiol reduces basal and cytokine induced monocyte adhesion to endothelial cells. Maturitas. 2002 Apr 25;41(4):313-9.
Mikkola TS, Anthony MS, Clarkson TB, St Clair RW. Serum cholesterol efflux potential in postmenopausal monkeys treated with tibolone or conjugated estrogens. Metabolism. 2002 Apr;51(4):523-30.
Lada AT, Willingham MC, St Clair RW. Triglyceride depletion in THP-1 cells alters cholesteryl ester physical state and cholesterol efflux. J Lipid Res. 2002 Apr;43(4):618-28.
Nordskog BK, Reagan JW Jr, St Clair RW. Sterol synthesis is up-regulated in cholesterol-loaded pigeon macrophages during induction of cholesterol efflux. J Lipid Res. 1999 Oct;40(10):1806-17.
Sulistiyani, St Clair RW. Effect of 17 beta-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture. Arterioscler Thromb Vasc Biol. 1997 Sep;17(9):1691-700.
Seo T, St Clair RW. Heparan sulfate proteoglycans mediate internalization and degradation of beta-VLDL and promote cholesterol accumulation by pigeon macrophages. J Lipid Res. 1997 Apr;38(4):765-79.