Atherosclerosis 174 (2004) 93–98 Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability Christophe Furman a , Corinne Copin a , Mejid Kandoussi a , Robert Davidson b , Martine Moreau c , Fergus McTaggart b , M. John Chapman c , Jean-Charles Fruchart a , Mustapha Rouis a,∗ a INSERM U-545 and Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille Cedex, France b AstraZeneca, Alderley Park, Cheshire, UK c INSERM U-551, H ˆ opital de la Pitié, Paris, France Received 16 January 2003; accepted 22 January 2004 Abstract 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor ® ), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC 50 of 70 nM. In addition, MMP-7 levels were re- duced in a dose-dependent manner with maximal inhibition of 50% (P< 0.01) at 1 M. Also, addition of isoprenoids such as farnesyl pyrophos- phate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5 ′ region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10 -6 M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Statin; Macrophages; MMPs; Pleiotropic 1. Introduction Atherosclerosis is a complex inflammatory process that can profoundly affect the structure and composition of the arterial wall. Mature human atherosclerotic plaques are fre- quently characterized by a lipid core covered by a fibrous cap composed of fibrillar collagens, elastin, proteoglycans, and smooth muscle cells (SMC). Inflammatory cells such as macrophages and T lymphocytes may also be present in these lesions [1]. Most sudden deaths due to acute myocardial infarction are caused by rupture of a coronary atheroma, particularly Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; HMDM, human monocyte-derived macrophages ∗ Corresponding author. Tel.: +33-3-20-87-77-52; fax: +33-3-20-87-73-60. E-mail address: mustapha.rouis@pasteur-lille.fr (M. Rouis). at sites where the fibrous cap is thin. Such rupture leads to hemorrhage into the plaque, thereby resulting in a prothrom- botic response, followed by rapid occlusion of the artery [2]. The accumulation of macrophage-derived foam cells in the vulnerable shoulder regions of atherosclerotic plaques [3] correlate with increased local release of matrix metallo- proteinases (MMPs) and weak fibrous cap tissue [4]. These findings suggest a potential role of macrophage-derived MMPs in the weakening and ultimate rupture of plaque structure. Several MMPs such as interstitial collagenase (MMP-1) [5], gelatinase-A (MMP-2) [6], gelatinase-B (MMP-9) [7], stromelysin-1 (MMP-3) [7], matrilysin (MMP-7) [8], macrophage metalloelastase-12 (MMP-12) [8], collagenase-3 (MMP-13) [9], and membrane-type MMP-1 (MMP-14) [10] have been localized to atheroscle- rotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.01.009