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 progression 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 activity and mRNA level, whereas platelet-derived growth factor (PDGF) showed a slight induction of the MMP-9 mRNA level. TNF-alpha treatment caused an increase in c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), and extracellular signal-regulated kinase (ERK) activities, whereas PDGF treatment caused an increase in ERKs and p38 MAPK activities without any effect on JNK activity. Treatment with either SB203580 (inhibitor of p38 MAPK) or U0126 (inhibitor of the ERK pathway) downregulated the TNF-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 arterial smooth muscle cells. Furthermore, suboptimal inhibitory concentrations of SB203580 and U0126 together almost completely inhibited the MMP-9 expression. These results suggest that p38 MAPK and ERK pathways contribute to the transcriptional regulation of MMP-9 in arterial smooth muscle cells.
Cho
A
A
Department of Pathology, University of Washington, Seattle 98195, USA. ascho@u.washington.edu
Graves
J
J
Reidy
M A
MA
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580