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Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1477-87. doi: 10.1161/ATVBAHA.112.248773. Epub 2012 Apr 5.

Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo.

Author information

1
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.

Abstract

OBJECTIVE:

Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo.

METHODS AND RESULTS:

Human endothelial cells were stimulated with thrombin (0.1-10 U/mL), CD40L (0.25-1 μg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold; P<0.001) and protein levels (4.5-fold; P<0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, α-CD40L, and α-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun N-terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP-10 and CD40L.

CONCLUSIONS:

Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications.

PMID:
22492089
DOI:
10.1161/ATVBAHA.112.248773
[Indexed for MEDLINE]

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