Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation
Articolo
Data di Pubblicazione:
2007
Citazione:
Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation / N. Ferri, G. Colombo, C. Ferrandi, E.W. Raines, B. Levkau, A. Corsini. - In: ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY. - ISSN 1079-5642. - 27:5(2007 May), pp. 1043-1049. [10.1161/ATVBAHA.107.139881]
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 micromol/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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
N. Ferri, G. Colombo, C. Ferrandi, E.W. Raines, B. Levkau, A. Corsini
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