Atherosclerosis 188 (2006) 51–58 Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages Niels R. Veillard 1 , Vincent Braunersreuther 1 , Claire Arnaud, Fabienne Burger, Graziano Pelli, Sabine Steffens, Franc ¸ois Mach ∗ Cardiology Division, Department of Medicine, Geneva University Hospital, Foundation for Medical Research, 64 Avenue Roseraie, 1211 Geneva, Switzerland Received 19 May 2005; received in revised form 23 September 2005; accepted 11 October 2005 Available online 29 November 2005 Abstract Objective: Atherosclerosis is a chronic immuno-inflammatory disease involving the recruitment of monocytes and T lymphocytes to the vascular wall of arteries. Chemokines and their receptors, known to induce leukocyte migration, have recently been implicated in atherogenesis. Recent in vitro and in vivo studies have suggested that statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors) have anti-inflammatory properties beyond their lipid-lowering effects. Thus, the aim of the present study was to investigate whether simvastatin reduces the expression of chemokines and chemokine receptors in two major cell types implicated in atherogenesis and to test isoprenoid intermediates involved in their regulation. Methods and results: We performed in vitro experiments on human vascular endothelial cells and human primary macrophages. First, we have shown by ELISA that 1 M simvastatin significantly reduced MCP-1 in endothelial cells (ECs) and macrophages stimulated with TNF- or IFN-, respectively. Messenger RNA analysis revealed that expression of the chemokines MCP-1, MIP-1 and MIP-1, as well as the chemokine receptors CCR1, CCR2, CCR4 and CCR5, was decreased by simvastatin, both in ECs and macrophages. Furthermore, the statin effects were reversed by mevalonate and mimicked by the geranylgeranyl transferase inhibitor (GGTI), whereas the farnesyl transeferase inhibitor (FTI) had no effect. These results suggests that statins act via inhibition of the geranylgeranylation of proteins. Conclusions: Our results demonstrate that statins reduce chemokine and chemokine receptor expressions in human ECs and macrophages via inhibition of the geranylgeranylpyrophosphate pathway. Thus, our data provide further evidence that statins have anti-inflammatory properties beyond their lipid-lowering effects. These findings highlight specific novel therapeutic targets for cardiovascular diseases to reduce inflammation mediated by chemokines and their receptors. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Inflammation; Statin; Chemokines 1. Introduction Over the past decades, atherosclerosis has been recog- nized as an inflammatory disease and established as the most common cause of death in western countries, responsible ∗ Corresponding author. Tel.: +41 22 382 7234; fax: +41 22 382 7245. E-mail address: Francois.Mach@medecine.unige.ch (F. Mach). 1 These authors equally contributed to this work. for half of the morbidity and mortality. Atherosclerotic lesions are characterized by accumulation of lipids, fibrous elements and immune infiltrates. Endothelial cells (ECs) and monocyte/macrophages are major cell types impli- cated during atherogenesis. During the whole process of atherogenesis, monocytes migrate through the endothelium and differentiate into foam cells within the neo-intima of the vessel wall [1]. Chemotactic cytokines or chemokines, are known to induce leukocyte migration, growth and 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.10.015