Mitogen-Activated Protein Kinases Mediate Matrix Metalloproteinase-9 Expression in Vascular Smooth Muscle Cells

Abstract

Abstract-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)-␣ 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-␣ 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-␣-induced MMP-9 expression in a dose-dependent manner. Treatment of cells with TNF-␣ and PDGF together stimulated the MMP-9 expression at a level higher than that observed with either factor alone, suggesting that TNF-␣ 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. Key Words: mitogen-activated protein kinases Ⅲ p38 mitogen-activated protein kinase Ⅲ extracellular signal-regulated kinase Ⅲ matrix metalloproteinase-9 Ⅲ tumor necrosis factor D egradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be important in the progression of atherosclerosis and plaque rupture. MMP-1, MMP-3, and MMP-9 have been identified in human atherosclerotic lesions, and the enhanced expression of MMP-9 at the shoulders of these lesions has been linked to plaque rupture. 1 In experimental animal models, MMPs are also shown to be important for smooth muscle cell migration into the intima. In a rat arterial injury model, after the initial medial smooth muscle cell replication, medial smooth muscle cells migrate and first appear in the intima 4 days after injury. 2 MMP-9 is expressed within 6 hours after injury in rat carotid arteries and continues to be expressed up to 6 days, whereas MMP-2 activity is markedly increased after 4 days of injury. 3 The importance of these MMPs in the migration of smooth muscle cells is illustrated by the finding that the administration of MMP inhibitor almost completely inhibits the number of smooth muscle cells migrating into the intima. 3 Although MMPs play an important role in lesion growth, little is known about the signaling mechanism involved in regulating MMP expression in vascular smooth muscle cells.Several growth factors and cytokines, such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-␣, and interleukin (IL)-1,...

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