Avasimibe and atorvastatin synergistically reduce cholesteryl ester content in THP-1 macrophages.
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.
Llaverías
Gemma
G
Unitat de Farmacologia, Departament de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain.
Jové
Mireia
M
Vázquez-Carrera
Manuel
M
Sánchez
Rosa M
RM
Díaz
Cristina
C
Hernández
Gonzalo
G
Laguna
Juan C
JC
Alegret
Marta
M
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology*; D000069059:Atorvastatin; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism*; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*
D000081:Acetamides; D000085:Acetates; D002788:Cholesterol Esters; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D000069059:Atorvastatin