Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages Gemma Llaverias, a V eronique No e, b Silvia Pe~ nuelas, b Manuel V azquez-Carrera, a Rosa M. S anchez, a Juan C. Laguna, a Carlos J. Ciudad, b,1 and Marta Alegret a, * ,1 a Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain b Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Spain Received 13 March 2004 Abstract With the aim of identifying new target genes that could contribute to limit foam cell formation, we analyzed changes in the pattern of gene expression in human THP-1 macrophages treated with atorvastatin and oxidized-LDL (oxLDL). To this end, we used a human cDNA array containing 588 cardiovascular-related cDNAs. Exposure to oxLDL resulted in differential expression of 26 genes, while coincubation with atorvastatin modified the expression of 29 genes, compared to treatment with oxLDL alone. Changes in the expression of candidate genes, potentially connected to the atherosclerotic process, were confirmed by quantitative RT-PCR and Western blot. We show that atorvastatin prevents the increase in the expression of scavenger receptor CD68 and that of fatty acid binding protein 4 caused by oxLDL. In addition, atorvastatin reduces the expression of HDL-binding protein, apo- lipoprotein E, and matrix metalloproteinase 9. These findings are relevant to understand the direct antiatherogenic effects of statins on macrophages. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Atorvastatin; oxLDL; THP-1; FABP4; CD68; HBP Atherosclerosis and its consequences (coronary heart disease and stroke) remain the leading cause of death in most industrialized countries [1]. The identification of lipoprotein abnormalities as a major risk factor for cardiovascular disease, specifically high levels of low density lipoprotein (LDL)-cholesterol, led to consider atherosclerosis primarily as a lipid disorder. However, atherogenesis involves also an inflammatory response in the arterial wall [2] and, nowadays, it is regarded as an inflammatory disease that develops in the context of hypercholesterolemia [3]. The disruption of the normal physiology of the vas- cular endothelium, also known as endothelial dysfunc- tion, is one of the earliest events in the atherosclerotic process [4]. The upregulation of cell-adhesion molecules [5] greatly increases the adherence of blood monocytes to the endothelium. After adhesion, monocytes migrate into the subendothelial space, where they differentiate into macrophages, a process that is accompanied by an increase in the surface expression of scavenger receptors. The uptake of oxidized-LDL (oxLDL) in a non-regu- lated manner leads to the accumulation of lipid droplets in the cytosol of macrophages, which are then trans- formed into foam cells. Today, the main pharmacological approach to reduce the risk for coronary heart disease is the correction of abnormally high plasma lipid levels [6]. The most effec- tive drugs to reduce plasma LDL-cholesterol are statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which significantly reduce cor- onary and total mortality in clinical trials [7]. However, the clinical benefit of these drugs is manifested early in the course of lipid-lowering therapy, before plaque re- gression could occur. Moreover, quantitative angio- graphic studies have shown that reversal of arterial narrowing occurs slowly and only to a small extent, despite a substantial decrease in cardiovascular events [8]. These findings led to the concept that statins may * Corresponding author. Fax: +34-93-403-5982. E-mail address: alegret@ub.edu (M. Alegret). 1 These authors have contributed equally to this paper. 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.04.021 Biochemical and Biophysical Research Communications 318 (2004) 265–274 BBRC www.elsevier.com/locate/ybbrc