Estradiol Suppresses MCP-1 Expression In Vivo

Implications for Atherosclerosis

From the Department of Obstetrics and Gynecology (S.P., R.S., G.C., L.N.), the Department of Molecular and Medical Pharmacology (R.S., G.C.), and the Department of Internal Medicine (M.N.), UCLA School of Medicine, University of California, Los Angeles, and the Department of Pathobiology and Program in Nutritional Sciences, University of Washington, Seattle (M.E.R.).

Correspondence to Lauren Nathan, MD, Department of Obstetrics and Gynecology, 27-139 CHS, UCLA School of Medicine, 10833 LeConte Ave, Los Angeles, CA 90095-1740.

Abstract—The mechanisms by which 17ß-estradiol retards atherogenesis are not known. The adhesion of monocytes to endothelial cells followed by the migration of monocytes into the artery wall are key cellular events that occur throughout the entire atherogenic process and may be responsive to estradiol. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is expressed in atherosclerotic lesions, is thought to play a major role in stimulating the migration of blood monocytes into developing atherosclerotic lesions. We therefore assessed the effects of estradiol in vivo on MCP-1 protein and mRNA expression in the descending thoracic aorta of rabbits fed a cholesterol-enriched (0.5%) diet for 6 weeks and in animals fed normal chow. MCP-1 protein was quantified by Western blot analysis and monocyte chemotaxis bioassay, and reverse transcription–polymerase chain reaction was used to ascertain the level of MCP-1 mRNA expression. We observed that in both ovary-intact and ovariectomized (OVX) animals, MCP-1 protein and mRNA expression were significantly increased by 6 weeks in animals fed a high-cholesterol diet. The cholesterol-induced increase in MCP-1 protein and mRNA expression was significantly attenuated in OVX rabbits supplemented with estradiol pellets (1.5- and 10.0-mg 60-day-release pellets), which yielded a range of estradiol concentrations encompassing the physiological levels. MCP-1 protein and mRNA expression were increased in normocholesterolemic OVX rabbits compared with normocholesterolemic ovary-intact animals, and this increase was prevented in OVX animals supplemented with estradiol pellets. Our observations indicate that both basal and hypercholesterolemia-induced increases in MCP-1 protein are modulated by physiological concentrations of estradiol.

Key Words: monocyte chemoattractant protein-1 • atherosclerosis • estrogen • estradiol

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