Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation
Abstract
Data di Pubblicazione:
2006
Citazione:
Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation / N. Ferri, G. Colombo, C. Ferrandi, B. Levkau, A. Corsini. - In: ATHEROSCLEROSIS SUPPLEMENTS. - ISSN 1567-5688. - 7:3(2006), pp. 157-157. ((Intervento presentato al 14. convegno 14th Meeting of the International-Society-of-Atherosclerosis tenutosi a Roma nel 2006.
Abstract:
In vivo and in vitro evidences suggest that activation of collagen receptors
(alpha2betal integrin and discoidin domain receptors) expressed in smooth
muscle cells (SMCs), by type I collagen, induces metalloproteinases (MMPs)
expression. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors,
statins, have been shown to interfere with integrin signaling but their effect on
MMP expression mediated by collagen receptors have not been investigated.
In the present study, we showed that simvastatin (3 umol/L) reduced MMP1
expression in human SMCs cultured on polymerized type I collagen, measured
by western blot analysis of both total cell lysates (-39.9-t-11.2%) and conditioned
media (-36.0-t-2.3%), but had no effect on MMP2 levels and activation.
Reduced MMP1 expression levels correlated with the inhibition of MMP1
promoter activity (-33.0-t-8.9%) and MMP1 mRNA levels (-37.8-t-10.5%), and
was associated with a strong decreased of smooth muscle collagen degradation
(-94.5-t-13.7%). Mevalonate, and the isoprenoid derivative geranylgeraniol,
substrate of protein geranylgeranyl transferases, completely prevented the
effect of simvastatin on MMP1 expression levels. Retroviral overexpression
of dominant negative mutants of geranylgeranylated Racl and Cdc42 led to
a reduction of protein and mRNA MMP1 levels, while dominant negative
RhoA had no effect. Finally, Racl activity was inhibited by simvastatin in
SMCs cultured on polymerized collagen. These results demonstrated that simvastatin,
by inhibiting Racl activity, reduced MMP1 expression and collagen
degradation in human SMCs.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
N. Ferri, G. Colombo, C. Ferrandi, B. Levkau, A. Corsini
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