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

A Cho1, J Graves, M A Reidy

  • 1Department of Pathology, University of Washington, Seattle 98195, USA. ascho@u.washington.edu

Arteriosclerosis, Thrombosis, and Vascular Biology
|December 16, 2000
PubMed

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.

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