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Two Antiatherogenic Effects of Progesterone on Human Macrophages; Inhibition of Cholesteryl Ester Synthesis and Block of Its Enhancement by Glucocorticoids¹

Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York, 11794

Address all correspondence and requests for reprints to: Nada A. Abumrad, Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661. E-mail: nadaa{at}physiology.pnb.sunysb.edu

The effects of progesterone and estradiol on cholesteryl ester (CE) formation by monocyte-derived human macrophages were examined. Formation was assessed from incorporation of ¹⁴C-cholesterol during a 20-h incubation with hormone and from that of ³H-oleate (3 h) after hormone removal. Progesterone inhibited cholesterol into CE and decreased CE cellular levels. Inhibition: 1) was reversed by progesterone removal; 2) was independent of the progesterone receptor (not blocked by the receptor antagonist RU40555); and 3) exhibited specific structural requirements; 11-OH-progesterone was inhibitory, whereas its stereoisomer 11ß-OH-progesterone was not. In contrast to progesterone, estradiol was ineffective. We had reported that dexamethasone enhanced CE accumulation by human macrophages (1). In this study, we describe similar effects of the endogenous steroid, cortisol, and of the most widely prescribed glucocorticoid, prednisolone. Both steroids increased CE formation from two folds, in the presence of cholesterol-liposomes, to five folds, in the presence of modified low-density lipoprotein. Progesterone (0.1–1 µmol/L), added during glucocorticoid treatment, blocked this increase. The progesterone block: 1) was duplicated by the steroid receptor inhibitor RU40555; 2) was not reversed by hormone removal; and 3) reflected inhibition of glucocorticoid-induced increases in messenger RNA for acyl-CoA-cholesterol:acyl transferase. Thus, progesterone exerted two effects on macrophages: it acutely inhibited CE formation, and it prevented glucocorticoid-induced increases in acyl-CoA-cholesterol-acyl transferase gene expression and CE synthesis.

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