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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1043.)
© 2007 American Heart Association, Inc.

Vascular Biology

Simvastatin Reduces MMP1 Expression in Human Smooth Muscle Cells Cultured on Polymerized Collagen by Inhibiting Rac1 Activation

Nicola Ferri; Giulia Colombo; Corrado Ferrandi; Elaine W. Raines; Bodo Levkau; Alberto Corsini

From the Department of Pharmacological Sciences (N.F., G.C., C.F., A.C.), University of Milan, Milan, Italy; Department of Pathology (E.W.R.), University of Washington, Seattle, Wash; Institute of Pathophysiology (B.L.), Center of Internal Medicine, University Hospital Essen, Essen, Germany.

Correspondence to Dr Nicola Ferri, Department of Pharmacological Sciences, Via Balzaretti 9, 20133, Milano, Italy. E-mail nicola.ferri{at}unimi.it

Objective— Activation of collagen receptors expressed by smooth muscle cells induces matrix metalloproteinase (MMP) expression. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to interfere with integrin signaling, but their effects on collagen receptor-mediated MMP expression have not been investigated.

Methods and Results— In the present study, we show that simvastatin (3 µmol/L) reduces MMP1 expression and secretion in human smooth muscle cells cultured on polymerized type I collagen by 39.9±11.2% and 36.0±2.3%, respectively. Reduced MMP1 protein levels correlate with a similar decrease in MMP1 promoter activity (–33.0±8.9%), MMP1 mRNA levels (–37.8±10.5%), and attenuation of smooth muscle cell collagen degradation (–34.2±6.1%). Mevalonate, and the isoprenoid derivative geranylgeraniol, precursors of geranylgeranylated proteins, completely prevent the inhibitory effect of simvastatin on MMP1. Moreover, the protein geranylgeranyltransferase inhibitor GGTI-286 significantly decreases MMP1 expression. Retroviral overexpression of dominant-negative mutants of geranylgeranylated Rac1 lead to a reduction of MMP1 protein (–50.4±5.4%) and mRNA levels (–97.9±1.0%), and knockdown of Rac1 by small interfering RNA downregulates MMP1 expression. Finally, simvastatin reduces GTP-bound Rac1 expression levels in smooth muscle cells cultured on polymerized collagen.

Conclusions— These results demonstrate that simvastatin, by inhibiting Rac1 activity, reduces MMP1 expression and collagen degradation in human smooth muscle cells.

Interaction of smooth muscle cells with polymerized collagen induces MMP1 expression. Here, we show that simvastatin inhibits MMP1 promoter activity, reduces MMP1 mRNA and protein levels and, finally, collagen degradation. These effects were also observed after the expression of either Rac1 dominant-negative or knockdown Rac1, a molecular target of simvastatin.

Key Words: atherosclerosis • integrins • matrix metalloproteinases • prenylated proteins • Rac1