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Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced

Josune Orbe1, José A Rodríguez, Olivier Calvayrac

  • 1Atherothrombosis Research Laboratory, Division of Cardiovascular Science, Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain.

Arteriosclerosis, Thrombosis, and Vascular Biology
|September 19, 2009
PubMed
Abstract

Insights

Thrombin significantly increases matrix metalloproteinase-10 (MMP-10) in endothelial cells via protease-activated receptor-1 (PAR-1) signaling. This finding reveals a new proinflammatory role for thrombin in vascular disorders.

Area of Science:

  • Vascular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Thrombin, a serine protease, drives vascular inflammation.
  • The impact of thrombin on endothelial matrix metalloproteinase-10 (MMP-10) expression was previously unknown.

Purpose of the Study:

  • To investigate the effect of thrombin on endothelial MMP-10 expression.
  • To elucidate the signaling pathways involved in thrombin-induced MMP-10 upregulation.

Main Methods:

  • Utilized protease-activated receptor-1 (PAR-1) agonists and blocking antibodies.
  • Analyzed extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways.
  • Performed promoter analysis, including site-directed mutagenesis and electrophoretic mobility shift assays.
  • Examined MMP-10 expression in murine endothelial cells and aorta, as well as in PAR-1-deficient mice.
  • Measured circulating MMP-10 levels in patients with disseminated intravascular coagulation and acute myocardial infarction.

Main Results:

  • Thrombin dose- and time-dependently increased endothelial MMP-10 mRNA and protein via PAR-1.
  • MMP-10 induction was dependent on ERK1/2, JNK pathways, and an AP-1 site in the MMP-10 promoter.
  • Thrombin upregulated MMP-10 in vivo in mice and in human patients with conditions of high thrombin generation.
  • PAR-1 deficiency abrogated thrombin's effect on MMP-10.

Conclusions:

  • Thrombin induces endothelial MMP-10 through a PAR-1-dependent pathway involving ERK1/2, JNK, and AP-1.
  • Endothelial MMP-10 upregulation represents a novel proinflammatory effect of thrombin.
  • Further research is warranted to explore the pathological implications in thrombin-related disorders and plaque stability.

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