Effects of probucol on cholesterol metabolism in mouse peritoneal macrophages: inhibition of HDL-mediated cholesterol efflux

Macrophage-derived foam cells are known to play an essential role in the de velopment and progression of atherosclerotic lesions. Probucol prevents oxi dative modification of low-density lipoprotein (LDL) and lowers plasma cont ents of LDL and high-density lipoprotein (HDL). A recent report using apoE -/- mice demonstrated that probucol treatment enhanced atherosclerosis in a poE -/- mice more rapidly than that in untreated apoE -/- mice, and a reduc tion in plasma cholesterol by probucol was not the cause of enhancement of atherosclerotic lesions in probucol-treated apoE -/- mice. Moreover, probuc ol was reported to inhibit apoA-I mediated cholesterol efflux from mouse ma crophages. These reports suggested that probucol might directly affect chol esterol metabolism in mouse macrophages. Thus, we investigated the effects of probucol on cholesterol metabolism in mouse resident peritoneal macropha ges. Probucol did not affect degradation of acetylated LDL (Ac-LDL), degrad ation of LDL and endogenous cholesterol synthesis in mouse macrophages. How ever, it significantly inhibited HDL-mediated cholesterol efflux. Moreover, probucol partially (30%) inhibited the binding of HDL to mouse macrophages , and significantly activated acyl-coenzyme A:cholesterol acyltransferase ( ACAT). Our results suggested that probucol inhibited HDL-mediated cholester ol efflux by inhibiting the binding of HDL to mouse macrophages and reducin g HDL-accessible free cholesterol content by ACAT activation, thereby worse ning atherosclerotic lesions in apoE -/- mice. However, it remains unclear whether probucol inhibits HDL-mediated cholesterol efflux from human macrop hages. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.