期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 32, 期 6, 页码 1477-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.248773
关键词
matrix metalloproteinase-10; endothelium; thrombin; CD40 ligand; microparticles
资金
- University of Navarra
- Ministerio de Ciencia e Innovacion (MICINN) [SAF2009-11949, SAF2009-12039, MICINN-PTQ-09-02-01941]
- Red Tematica de Investigacion Cardiovascular RECAVA [RD06/0014/0008, RD06/0014/0027]
- Instituto de Salud Carlos III (Madrid, Spain) [FIS/PS09/00143, FIS/PI-10-01572, I3SNS-INT-11-063]
- Education Department, Gobierno de Navarra
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 mu g/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, alpha-protease-activated receptor-1, alpha-CD40L, and alpha-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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2012;32:1477-1487.)
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