The proliferation and migration of arterial smooth muscle cells
(SMCs) are key events in the vascular restenosis that frequently follows
angioplasty. Furthermore, SMC migration and neointimal
hyperplasia are promoted by degradation of the extracellularmatrix by
matrix metalloproteinases (MMPs). Because we demonstrated previously
that the proinflammatory and proatherogenic cytokine
interleukin-18 (IL-18) stimulates SMC proliferation (Chandrasekar,
B., Mummidi, S., Valente, A. J., Patel, D. N., Bailey, S. R.,
Freeman, G. L., Hatano, M., Tokuhisa, T., and Jensen, L. E. (2005)
J. Biol. Chem. 280, 26263–26277), we investigated whether IL-18
induces SMC migration in an MMP-dependent manner and
whether the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor
atorvastatin can inhibit this response. IL-18 treatment increased
both mRNA and protein expression of MMP9 in human coronary
artery SMCs. Gel shift, enzyme-linked immunosorbent, and chromatin
immunoprecipitation assays revealed a strong induction of
IL-18-mediated AP-1 (c-Fos, c-Jun, and Fra-1) and NF- B (p50 and
p65) activation and stimulation of MMP9 promoter-dependent
reporter gene activity in an AP-1- and NF- B-dependent manner.
Ectopic expression of p65, c-Fos, c-Jun, and Fra-1 induced MMP9
promoter activity. Specific antisense or small interfering RNA
reagents for these transcription factors reduced IL-18-mediated
MMP9 transcription. Furthermore, IL-18 stimulated SMC migration
in an MMP9-dependent manner. Atorvastatin effectively suppressed
IL-18-mediated AP-1 and NF- B activation,MMP9 expression,
and SMC migration. Together, our results indicate for the first
time that the proatherogenic cytokine IL-18 induces human coronary
artery SMC migration in an MMP9-dependent manner. Atorvastatin
inhibits IL-18-mediated aortic SMC migration and has
therapeutic potential for attenuating the progression of atherosclerosis
and restenosis.

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