TY - JOUR
T1 - Simvastatin reduces MMP1 expression in human smooth muscle cells cultured on polymerized collagen by inhibiting Rac1 activation
AU - Ferri, Nicola
AU - Colombo, Giulia
AU - Ferrandi, Corrado
AU - Raines, Elaine W.
AU - Levkau, Bodo
AU - Corsini, Alberto
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Integrins
KW - Matrix metalloproteinases
KW - Prenylated proteins
KW - Rac1
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U2 - 10.1161/ATVBAHA.107.139881
DO - 10.1161/ATVBAHA.107.139881
M3 - Article
C2 - 17303772
AN - SCOPUS:34247347733
VL - 27
SP - 1043
EP - 1049
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 5
ER -