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Article Dans Une Revue Arteriosclerosis, Thrombosis, and Vascular Biology Année : 2012

Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo

Sara Martínez de Lizarrondo
  • Fonction : Auteur
Carmen Roncal
  • Fonction : Auteur
Cristina Rodríguez
  • Fonction : Auteur
Nerea Varo
  • Fonction : Auteur
Ana Purroy
  • Fonction : Auteur
Leonardo Lorente
  • Fonction : Auteur
José A Rodríguez
  • Fonction : Auteur
Loïc Doeuvre
  • Fonction : Auteur
Sandra Hervás-Stubbs
  • Fonction : Auteur
Eduardo Anglés-Cano
José A Páramo
  • Fonction : Auteur
José Martínez-González
  • Fonction : Auteur
Josune Orbe
  • Fonction : Auteur
  • PersonId : 1083092

Résumé

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 mg/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, -protease-activated receptor-1, -CD40L, and -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 (n560) 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.
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hal-03026076 , version 1 (26-11-2020)

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Sara Martínez de Lizarrondo, Carmen Roncal, Olivier Calvayrac, Cristina Rodríguez, Nerea Varo, et al.. Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 2012, 32 (6), pp.1477-1487. ⟨10.1161/ATVBAHA.112.248773⟩. ⟨hal-03026076⟩
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