Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells

Expression of matrix metalloproteinase (MMP)-9 has been linked to the progr ession of plaque rupture and intimal formation in arterial lesions. In this study, we determined which factors and signaling pathways are involved in regulating the MMP-9 gene. Rat carotid arterial smooth muscle cells treated with tumor necrosis factor (TNF)-alpha showed a marked increase in MMP-9 a ctivity and mRNA level, whereas platelet-derived growth factor (PDGF) showe d a slight induction of the MMP-9 mRNA level. TNF-cr treatment caused an in crease in c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kina se (p38 MAPK), and extracellular signal-regulated kinase (ERK) activities, whereas PDGF treatment caused an increase in ERKs and p38 MAPK activities w ithout any effect on JNK activity. Treatment with either SB203580 (inhibito r of p38 MAPK) or U0126 (inhibitor of the ERK pathway) downregulated the TN F-alpha -induced MMP-9 expression in a dose-dependent manner. Treatment of cells with TNF-alpha and PDGF together stimulated the MMP-9 expression at a level higher than that observed with either factor alone, suggesting that TNF-alpha and PDGF have a synergistic effect on MMP-9 expression in arteria l smooth muscle cells. Furthermore, suboptimal inhibitory concentrations of SB203580 and U0126 together almost completely inhibited the MMP-9 expressi on. These results suggest that p38 MAPK and ERK pathways contribute to the transcriptional regulation of MMP-9 in arterial smooth muscle cells.