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Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells
1Department of Pathology, University of Washington, Seattle 98195, USA. ascho@u.washington.edu
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)-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.
Insights
Tumor necrosis factor-alpha and platelet-derived growth factor synergistically increase matrix metalloproteinase (MMP)-9 expression in arterial smooth muscle cells. The p38 MAPK and ERK pathways are key regulators of MMP-9 gene transcription.
Area of Science:
- Vascular Biology
- Molecular Biology
- Cell Signaling
Background:
- Matrix metalloproteinase (MMP)-9 expression is implicated in arterial lesion progression, including plaque rupture and intimal hyperplasia.
- Understanding the regulation of MMP-9 is crucial for developing therapeutic strategies against cardiovascular diseases.
Purpose of the Study:
- To investigate the factors and signaling pathways that regulate matrix metalloproteinase (MMP)-9 gene expression in rat carotid arterial smooth muscle cells.
- To elucidate the roles of tumor necrosis factor-alpha (TNF-alpha) and platelet-derived growth factor (PDGF) in MMP-9 regulation.
- To identify the specific mitogen-activated protein kinase (MAPK) pathways involved in MMP-9 transcriptional control.
Main Methods:
- Treatment of rat carotid arterial smooth muscle cells with TNF-alpha and/or PDGF.
- Assessment of MMP-9 activity and mRNA levels.
- Measurement of c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK) activities.
- Inhibition of p38 MAPK and ERK pathways using SB203580 and U0126, respectively.
Main Results:
- TNF-alpha significantly increased MMP-9 activity and mRNA, while PDGF showed a modest induction.
- TNF-alpha activated JNK, p38 MAPK, and ERK; PDGF activated ERK and p38 MAPK but not JNK.
- Inhibition of p38 MAPK or ERK pathways downregulated TNF-alpha-induced MMP-9 expression.
- Combined TNF-alpha and PDGF treatment exhibited a synergistic effect on MMP-9 expression.
- Combined inhibition of p38 MAPK and ERK pathways nearly abolished MMP-9 expression.
Conclusions:
- Both TNF-alpha and PDGF contribute to MMP-9 upregulation in arterial smooth muscle cells, with a synergistic interaction between them.
- The p38 MAPK and ERK signaling pathways are critical mediators of MMP-9 transcriptional regulation.
- Targeting these MAPK pathways may offer a therapeutic approach to control MMP-9 expression in vascular diseases.