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ERK1/2 mediates TNF‐α‐induced matrix metalloproteinase‐9 expression in human vascular smooth muscle cells via the regulation of NF‐κB and AP‐1: Involvement of the ras dependent pathway

The expression of matrix metalloproteinase‐9 (MMP‐9) has been implicated in progression of atherosclerotic lesions. The role and importance of the signaling pathway in the transcriptional regulation of MMP‐9 in human aortic smooth muscle cells (HASMC) was examined. Tumor necrosis factor‐α (TNF‐α) stimulated the secretion of MMP‐9 in HASMC, as shown by zymography and immunoblot analysis. At the transcriptional levels, TNF‐α also stimulated the 5′‐flanking 710‐bp promoter activity of MMP‐9. Transcription factors NF‐κB binding site (−601) and AP‐1 binding site (−82) were identified as the cis‐elements for TNF‐α activation, as determined by gel shift assay and mutation analysis. Treatment with U0126, an inhibitor of the extracellular signal‐regulated kinase (ERK), significantly downregulated TNF‐α‐induced MMP‐9 expression and promoter activity, whereas the inactive analog U0124 had no effect. Furthermore, the transactivation of TNF‐α‐stimulated NF‐κB and AP‐1 was inhibited by U0126 treatment. Finally, the transient transfection of HASMC with dominant negative Ras (RasN17) suppressed TNF‐α‐induced ERK activity, MMP‐9 production, and promoter activity. Overexpression of RasN17 also abolished the TNF‐α‐stimulated NF‐κB and AP‐1 activity. In conclusion, the findings herein indicate the activation of the Ras/ERK pathway contributes to the induction of MMP‐9 expression in HASMC. In addition, the transcription factors NF‐κB and AP‐1 that are involved in the Ras/ERK‐mediated control of MMP‐9 regulation on HASMC in response to TNF‐α have now been identified. J. Cell. Physiol. 198: 417–427, 2004© 2003 Wiley‐Liss, Inc.