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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1043-1049
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume27
Issue number5
DOIs
Publication statusPublished - May 2007

Keywords

  • Atherosclerosis
  • Integrins
  • Matrix metalloproteinases
  • Prenylated proteins
  • Rac1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation'. Together they form a unique fingerprint.

  • Cite this