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Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo
14 auth. Sara Martínez de Lizarrondo, C. Roncal, O. Calvayrac, C. Rodríguez, N. Varo, A. Purroy, L. Lorente, J. Rodríguez, Loïc Doeuvre, S. Hervás-Stubbs, ...
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 endothel…
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 &mgr;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, a-protease-activated receptor-1, &agr;-CD40L, and &agr;-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.
Published in
Arteriosclerosis, Thrombosis and Vascular Biology
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9
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5 | 2012 |
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