Interleukin-18-induced Human Coronary Artery Smooth Muscle Cell Migration Is Dependent on NF-κB- and AP-1-mediated Matrix Metalloproteinase-9 Expression and Is Inhibited by Atorvastatin

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 extracellular matrix 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-κB (p50 and p65) activation and stimulation of MMP9 promoter-dependent reporter gene activity in an AP-1- and NF-κB-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-κB 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. 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 extracellular matrix 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-κB (p50 and p65) activation and stimulation of MMP9 promoter-dependent reporter gene activity in an AP-1- and NF-κB-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-κB 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. Atherosclerosis is considered to be a chronic inflammatory disease characterized by enhanced expression of proinflammatory cytokines, chemokines, and adhesion molecules (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar). The cross-talk between cytokines, chemokines, and infiltrating immune cells amplifies the inflammatory cascade in the vessel wall, resulting in atherogenesis (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar). Interleukin-18 (IL-18) 3The abbreviations used are: IL-18, interleukin-18; SMC, smooth muscle cell; ECM, extracellular matrix; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of matrix metalloproteinases; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; IL-18Rα, interleukin-18 receptor-α; PI3K, phosphatidylinositol 3-kinase; ODNs, oligodeoxynucleotides; siRNA, small interfering RNA; dn, dominant-negative; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation; GFP, green fluorescent protein. is a proinflammatory and proatherogenic cytokine that induces the expression of other proinflammatory cytokines and adhesion molecules (4Dinarello C.A. Eur. Cytokine Netw. 2000; 11: 483-486PubMed Google Scholar). IL-18 has been localized to human atherosclerotic lesions (5Mallat Z. Corbaz A. Scoazec A. Besnard S. Leseche G. Chvatchko Y. Tedgui A. Circulation. 2001; 104: 1598-1603Crossref PubMed Scopus (522) Google Scholar, 6Gerdes N. Sukhova G.K. Libby P. Reynolds R.S. Young J.L. Schonbeck U. J. Exp. Med. 2002; 195: 245-257Crossref PubMed Scopus (445) Google Scholar), and circulating IL-18, which is increased in acute coronary syndromes (7Mallat Z. Henry P. Fressonnet R. Alouani S. Scoazec A. Beaufils P. Chvatchko Y. Tedgui A. Heart. 2002; 88: 467-469Crossref PubMed Scopus (137) Google Scholar), has been shown to predict future cardiovascular events (7Mallat Z. Henry P. Fressonnet R. Alouani S. Scoazec A. Beaufils P. Chvatchko Y. Tedgui A. Heart. 2002; 88: 467-469Crossref PubMed Scopus (137) Google Scholar). A positive correlation between serum IL-18 levels and carotid intima-media thickness has been demonstrated (8Yamagami H. Kitagawa K. Hoshi T. Furukado S. Hougaku H. Nagai Y. Hori M. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1458-1462Crossref PubMed Scopus (114) Google Scholar). Administration of IL-18 aggravates atherosclerosis in mice (9Whitman S.C. Ravisankar P. Daugherty A. Circ. Res. 2002; 90: E34-E38Crossref PubMed Google Scholar). Moreover, atherogenesis is reduced in IL-18-deficient apoE knock-out mice (10Elhage R. Jawien J. Rudling M. Ljunggren H.G. Takeda K. Akira S. Bayard F. Hansson G.K. Cardiovasc. Res. 2003; 59: 234-240Crossref PubMed Scopus (315) Google Scholar), suggesting a causal role for IL-18 in the development and progression of atherosclerosis. Recently, we demonstrated that IL-18 induces human aortic smooth muscle cell (SMC) proliferation (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). However, it is not known whether IL-18 induces SMC migration. Both migration and proliferation play a role in normal and diseased vessels (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar). SMC migration contributes to normal angiogenesis. However, SMC migration also plays a causal role in pathological remodeling of the vessel walls during atherosclerosis, arteriosclerosis, and restenosis following angioplasty (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar). Vessel wall remodeling is characterized by a disruption in the delicate balance between extracellular matrix (ECM) deposition and degradation, with matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases (TIMPs)) playing a prominent role. MMPs are zinc-dependent proteases and are classified as collagenases, stromelysins, elastases, and expression is both the and are as and are following and MMP9 the Circ. Res. 2002; 90: PubMed Scopus Google Scholar). activation of and of expression and activation, results in of the and can to pathological remodeling and vascular restenosis Circ. Res. 2002; 90: PubMed Scopus Google Scholar, U. K. 2003; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar, A. Circ. Res. 2002; PubMed Scopus Google Scholar). Because increased matrix degradation SMC migration A. Circ. Res. 2002; PubMed Scopus Google Scholar), we that IL-18 induces SMC migration induction of that IL-18 SMC migration in an MMP9-dependent manner. IL-18 induced MMP9 expression activation of AP-1 and NF-κB that a inhibitor of 3-hydroxy-3-methylglutaryl-CoA inhibits IL-18-mediated SMC migration by attenuating AP-1 and NF-κB activation and MMP9 human IL-18 tumor necrosis and and IL-18 and normal NF-κB and and muscle and other Atorvastatin a human coronary artery and in by the the with serum a human IL-18 and for the time the of the and and whether IL-18 induces arterial SMC migration or is by as TNF-α, and IFN-γ, cells with the for to IL-18 a as a The of these in assays SMC with the or B. K. M. Jensen L.E. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). as a B. K. M. Jensen L.E. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). cells with or for by the of the human protein TNF-α, or for an The as an and and the reporter and a (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, B. K. M. Jensen L.E. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for by activity by the activity and are as stimulation for a in cells as by RNA and antisense used as TNF-α, c-Fos, c-Jun, Fra-1 and or and MMP9 expression by and N. F. M. A. S. R. A. Circulation. PubMed Scopus Google Scholar, J. S. B. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). that not in the human as a and by expression B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A used as a of by NF-κB activation also by with the of B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The as a expression by in B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for in cells with the The of and to be Ectopic expression of p65, c-Fos, c-Jun, and Fra-1 the expression in a is and is B. A.J. Freeman G.L. L. Mummidi S. Res. PubMed Scopus Google Scholar). with green fluorescent protein used as a the role of and in IL-18-mediated MMP9 expression, with in in or to the of migration and with a of and in and serum and the stimulated with IL-18 The IL-18 the for with and cells the to the of the the B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the role of MMPs in IL-18-mediated cell with in in and in for to the of with for to the of the of atorvastatin with atorvastatin the for to IL-18 as a and following and by B. K. M. Jensen L.E. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the B. S. Mummidi S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and and AP-1 by and of the The of NF-κB and AP-1 an B. A.J. Freeman G.L. L. Mummidi S. Res. PubMed Scopus Google Scholar). The assays to the The is the of transcription factors in and used in human MMP9 activity and NF-κB AP-1 in a IL-18-mediated NF-κB and AP-1 activation also in assays transcription reporter and with IL-18 as a The used as a as in and to serum and IL-18 the and for The immunoprecipitation following the (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). The of an immunoprecipitation in the of used as the of a of the in by the MMP9 that a used as the of mRNA RNA and for and MMP9 K. K. Nagai N. K. J. 2000; Google Scholar, L. S.C. 2005; PubMed Scopus Google Scholar). (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. 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PubMed Scopus Google Scholar). muscle used as an and and and in the by an matrix following the and by between and we MMP9 levels in by an a the of the human to both the and of levels in and by as by F. 2001; PubMed Scopus Google Scholar). with the in to the and to activity and for in of and for in and with and in of activity as a MMP9 of the of the MMP9 gene human as previously C.A. 2005; PubMed Scopus Google the in The a the The antisense a The and the reporter in the The of the by both A of the in of the and in the MMP9 by the and the in and by between and by of with assays and the in the indicate the IL-18 SMC whether IL-18 induces SMC we used A in cell migration following IL-18 treatment Because IL-18 is a of TNF-α, and (4Dinarello C.A. Eur. Cytokine Netw. 2000; 11: 483-486PubMed Google and as these cytokines play a role in atherogenesis (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar), we investigated whether SMC migration is by these with the for to IL-18 treatment to cell migration. of IL-18 with for cell migration. of the in assays NF-κB and activation reporter gene The results in that and the reporter gene for TNF-α, and IL-18 and and activation for However, and to IL-18-mediated NF-κB reporter gene activity results indicate that IL-18 is a of SMC migration and of the proinflammatory cytokines TNF-α, and IL-18 and MMP9 migration follows matrix degradation by MMPs, we for the expression of MMPs and in the SMC an that MMPs and with or IL-18 for and used to the extracellular matrix The for of the to the The results indicate IL-18 stimulated of the and it other MMPs or TIMPs, suggesting that IL-18 induces matrix degradation by and MMP9 IL-18 SMC and IL-18 stimulated and MMP9 we investigated whether their activity IL-18-mediated SMC migration. inhibits activation of both and of and MMP9 IL-18-mediated SMC migration and inhibitors and the to IL-18-mediated cell the of and MMP9 in IL-18-mediated SMC migration. between the and MMP9 we and MMP9 expression The of these has been demonstrated previously N. F. M. A. S. R. A. Circulation. PubMed Scopus Google Scholar, J. S. B. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). or not cell not The of both and MMP9 IL-18-mediated SMC migration of mRNA is shown However, of MMP9 that of the other treatment with SMC migration. Together, these results indicate both and MMP9 SMC migration MMP9 plays a role in IL-18-mediated SMC migration IL-18 MMP9 in MMP9 expression be the levels of gene transcription and activation and we whether IL-18 stimulates MMP9 mRNA expression and activation and in SMCs. IL-18 MMP9 mRNA expression in a manner The in MMP9 mRNA expression and levels with in IL-18 used time a in MMP9 mRNA expression and for to MMP9 in a or is by a of cell The is to MMP9 by of the we both the and of MMP9 in SMC by the of MMP9 with IL-18 not IL-18 induced the activation of MMP9 as by increased levels of the results by an that both the and of MMP9 increased levels of the of MMP9 following IL-18 treatment Together, these results that IL-18 MMP9 in both by increased mRNA expression and by activation of the protein IL-18 MMP9 in an AP-1- and NF-κB-dependent IL-18 induced MMP9 mRNA expression, we investigated whether IL-18 MMP9 expression the we investigated whether IL-18 induces MMP9 gene transcription NF-κB and both of which been previously in MMP9 gene H. M. Google Scholar). with an MMP9 both the and treatment with IL-18 not IL-18 a in reporter gene activity Furthermore, with or or with antisense to the not or in MMP9 suggesting a by the whether MMP9 transcription is and we cells with MMP9 or both of the NF-κB and AP-1 results the the both NF-κB and AP-1 activity to that of the suggesting that both NF-κB and AP-1 play a role in IL-18-mediated MMP9 transcription. these with in the NF-κB or AP-1 A in the reporter activity the NF-κB or AP-1 However, the both that IL-18 induces MMP9 transcription in NF-κB and AP-1 transcription factors IL-18 NF-κB MMP9 promoter activity reduced following or of the potential NF-κB or AP-1 in the we whether these in NF-κB and AP-1 in and in following IL-18 with the and the MMP9 promoter that or with IL-18 for IL-18 induced a in NF-κB activity in the and the used in and a of we also that IL-18 induced NF-κB activation in a NF-κB shift not Because the of NF-κB we the induction of of NF-κB by IL-18 that IL-18 increased and in the SMC protein However, and levels not by IL-18 Because IL-18 induced NF-κB we investigated whether NF-κB in with the MMP9 assays arterial that or with demonstrated that IL-18 treatment increased to the NF-κB in investigated the role of NF-κB in MMP9 transcription. The results in that of or or with MMP9 transcription. of and in cell by expression of or induced MMP9 transcription Together, these results that IL-18-mediated MMP9 transcription is NF-κB-dependent IL-18 AP-1 IL-18-mediated MMP9 activity reduced a AP-1 used or the we investigated whether IL-18 stimulates AP-1 activation in SMCs. levels of AP-1 activity in cells a in AP-1 activity following IL-18 treatment the used in EMSA, and results used not of revealed a in c-Fos, and to in and and levels not by IL-18 Because IL-18 induced AP-1 we investigated whether AP-1 in with the MMP9 assays arterial that or with demonstrated that IL-18 treatment increased Fra-1 to the AP-1 in investigated whether AP-1 MMP9 transcription. The results in that antisense of c-Fos, c-Jun, and Fra-1 MMP9 transcription. expression of c-Fos, c-Jun, and Fra-1 induced MMP9 transcription that Fra-1 is and in MMP9 promoter activity. Together, these results that IL-18-mediated MMP9 transcription is IL-18 AP-1 and NF-κB and demonstrated that IL-18 NF-κB and shown previously that IL-18 induces and activation (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, B. Mummidi S. R. M. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). investigated whether IL-18-mediated NF-κB and AP-1 activation is and activation by the inhibitors as as by of in the expression by and of results indicate with the or green fluorescent protein to treatment with and and of or IL-18-mediated NF-κB and AP-1 that IL-18 induces NF-κB and AP-1 activation and Atorvastatin SMC are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase Full Text Full Text PDF PubMed Scopus Google Scholar, F. Cardiovasc. Med. 2005; PubMed Scopus Google Scholar). Atorvastatin serum levels and has been used in to and to inhibit atherogenesis in human coronary D. R. E. Circ. Res. 2002; PubMed Scopus Google Scholar, M. A. J. H. 2003; PubMed Scopus Google Scholar, B. G. Res. PubMed Scopus Google Scholar). whether atorvastatin can inhibit SMC a of atherogenesis and with atorvastatin for migration. of SMC migration the and IL-18 the of IL-18 and atorvastatin induced cell However, the as a positive induced cell the in the of atorvastatin transcription activation with atorvastatin IL-18-mediated and NF-κB-dependent reporter gene Furthermore, atorvastatin IL-18-mediated MMP9 transcription mRNA expression and activity Together, these results indicate that atorvastatin is a inhibitor of IL-18-mediated MMP9 expression and SMC migration that the proinflammatory and proatherogenic cytokine IL-18 can human coronary artery SMC migration of other proinflammatory IL-18 induced the transcription and mRNA expression of MMP9 a and AP-1- and and stimulated the of Atorvastatin IL-18-mediated and MMP9 expression and SMC migration results a causal role for IL-18 in atherogenesis and the therapeutic potential of atorvastatin for the of IL-18-mediated and MMP9-dependent SMC migration. SMC migration and proliferation are of both normal vessel and vascular (1Ross R. Am. Heart J. 1999; 138: S419-S420Crossref PubMed Google Scholar, 2Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19647) Google Scholar, 3Libby P. Nature. 2002; 420: 868-874Crossref PubMed Scopus (7135) Google Scholar). and hyperplasia are characterized by the proliferation of in the and their migration the normal are to the with of the to this with the the expression, activation, and of cytokines, chemokines, and adhesion molecules by the cells Circ. Res. 2002; 90: PubMed Scopus Google Scholar, U. K. 2003; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar, A. Circ. Res. 2002; PubMed Scopus Google Scholar). expression, and degradation are by a balance between and The disruption of this delicate balance in of activation results in degradation and induction of SMC and migration Circ. Res. 2002; 90: PubMed Scopus Google Scholar, U. K. 2003; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar, A. Circ. Res. 2002; PubMed Scopus Google Scholar). MMPs are zinc-dependent proteases that are classified as collagenases, stromelysins, elastases, and expression is both the and are as and are following and MMP9 the MMPs with activity The activation of and MMP9 results in of the and to pathological remodeling and vascular restenosis U. K. 2003; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar, A. Circ. Res. 2002; PubMed Scopus Google Scholar, D. R. E. Circ. Res. 2002; PubMed Scopus Google Scholar). IL-18 is a cytokine with proinflammatory and proatherogenic with atherosclerotic vascular an of IL-18 is a strong of (7Mallat Z. Henry P. Fressonnet R. Alouani S. Scoazec A. Beaufils P. Chvatchko Y. Tedgui A. Heart. 2002; 88: 467-469Crossref PubMed Scopus (137) Google and is with carotid intima-media thickness (8Yamagami H. Kitagawa K. Hoshi T. Furukado S. Hougaku H. Nagai Y. Hori M. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1458-1462Crossref PubMed Scopus (114) Google Scholar), suggesting a causal role for IL-18 in the development and progression of atherosclerosis. these an between increased IL-18 levels and atherosclerosis, it is whether IL-18 plays a role in SMC migration and Recently, we demonstrated that IL-18 a proliferation expression (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). the we shown that IL-18 induces SMC migration the induction of AP-1- and MMP9 expression, which is in and Because activation our results that IL-18 is to their proliferation (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google and migration. to MMP9 expression, IL-18 also induced an that extracellular matrix we that IL-18 stimulated and MMP9 expression results been in in which IL-18 stimulated MMP9 levels M. A. J. H. 2003; PubMed Scopus Google Scholar), suggesting that IL-18 the balance in of expression and induces results also the of and MMP9 inhibits IL-18-mediated SMC the are MMP9 expression is that MMP9 play a role in IL-18-mediated SMC migration. results and the of B. G. Res. PubMed Scopus Google Scholar), that IL-18 stimulates cell migration in an MMP9-dependent manner. However, in this the for IL-18-mediated MMP9 expression not results also that IL-18 stimulates MMP9 expression both the and IL-18 stimulated MMP9 mRNA expression, and the in IL-18-mediated MMP9 expression that AP-1 and NF-κB activation for these of revealed that IL-18 induced AP-1 c-Fos, c-Jun, and Fra-1 and an NF-κB and expression of c-Fos, c-Jun, and Fra-1 stimulated MMP9 antisense of c-Fos, c-Jun, and Fra-1 MMP9 transcription. of and stimulated MMP9 expression, and MMP9 results that both AP-1 and NF-κB are of IL-18-mediated MMP9 gene transcription. with and c-Jun, Fra-1 levels in Furthermore, Fra-1 antisense and antisense in IL-18-mediated MMP9 are of Fra-1 has been shown to and in cell K. N. F. D. 2005; PubMed Scopus Google Scholar). is that Fra-1 in a in SMC migration. reductase are used in to and to the in with coronary artery Full Text Full Text PDF PubMed Scopus Google Scholar, F. Cardiovasc. Med. 2005; PubMed Scopus Google Scholar, P. H. J. N. Engl. J. 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Cytokine Res. 2005; 25: PubMed Scopus Google Scholar), that atorvastatin also and The results of our for potential in cardiovascular expression of IL-18 or atherosclerosis and restenosis. progression of the by IL-18-mediated activation and Because atorvastatin IL-18-mediated NF-κB and AP-1 activation in it also inhibit and in proatherogenic cytokine and induction and their NF-κB activation is a in the that results Atorvastatin inhibit this response. expression and degradation, IL-18 the of as a of and is of the of in both and Atorvastatin inhibit this and with our results indicate in to a SMC (11Chandrasekar B. Mummidi S. Valente A.J. Patel D.N. Bailey S.R. Freeman G.L. Hatano M. Tokuhisa T. Jensen L.E. J. Biol. Chem. 2005; 280: 26263-26277Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), the proinflammatory and proatherogenic cytokine IL-18 also induces SMC migration AP-1- and NF-κB-dependent MMP9 Atorvastatin inhibits IL-18-mediated SMC migration by attenuating AP-1 and NF-κB activation and MMP9 The of atorvastatin MMP9 expression both the and The migration of atorvastatin and a therapeutic for attenuating the progression of atherosclerosis and restenosis. G. L. Freeman for and of the the of