Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation.
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.


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.
Ferri
Nicola
N
Department of Pharmacological Sciences, University of Milan, Milano, Italy. nicola.ferri@unimi.it
Colombo
Giulia
G
Ferrandi
Corrado
C
Raines
Elaine W
EW
Levkau
Bodo
B
Corsini
Alberto
A
D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007231:Infant, Newborn; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics*; D061965:Matrix Metalloproteinase Inhibitors; D008798:Mevalonic Acid / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
C437105:GGTI 286; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C107953:RAC1 protein, human; D012333:RNA, Messenger; D003094:Collagen; D019821:Simvastatin; D020781:Matrix Metalloproteinase 1; D020830:rac1 GTP-Binding Protein; D007930:Leucine; D008798:Mevalonic Acid