European Journal of Pharmacology 2002-09-06

Avasimibe and atorvastatin synergistically reduce cholesteryl ester content in THP-1 macrophages.

Gemma Llaverías, Mireia Jové, Manuel Vázquez-Carrera, Rosa M Sánchez, Cristina Díaz, Gonzalo Hernández, Juan C Laguna, Marta Alegret

Index: Eur. J. Pharmacol. 451(1) , 11-7, (2002)

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Abstract

Evidence suggests that the inhibition of both acyl-CoA:cholesterol acyltransferase and hydroxymethyl glutaryl-CoA reductase causes a synergistic direct antiatherosclerotic effect on the vessel wall. To investigate this synergism in a single cell type and to avoid the confounding effect of plasma cholesterol lowering by these drugs, we have used an in vitro model of human macrophages (phorbol ester-treated THP-1 cells). In macrophages incubated simultaneously with acetyl low-density lipoproteins, the novel acyl-CoA:cholesterol acyltransferase inhibitor avasimibe (0.01-0.5 microM) caused a concentration-dependent reduction in cell cholesteryl ester content that was not accompanied by an increase in intracellular free cholesterol. A 5 microM concentration of atorvastatin enhanced by approximately twofold the ability of 0.5 microM avasimibe to reduce the mass of esterified cholesterol, and this was reversed by co-incubation with 200 microM mevalonate or 10 microM geranyl-geraniol. Based on these data, we propose that the synergism between acyl-CoA:cholesterol acyltransferase and hydroxymethyl glutaryl-CoA reductase inhibitors found in several in vivo studies may be explained by a direct additive effect of both agents reducing the lipid content of the macrophages present in the lesion area.Copyright 2002 Elsevier Science B.V.