Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
Por:
De Lizarrondo S.M., Roncal C., Calvayrac O., Rodríguez C., Varo N., Purroy A., Lorente L., Rodríguez J.A., Doeuvre L., Hervás-Stubbs S., Angles-Cano E., Páramo J.A., Martínez-González J., Orbe J.
Publicada:
1 ene 2012
Resumen:
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, a-CD40L, and a-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. © 2012 American Heart Association, Inc.
Filiaciones:
De Lizarrondo S.M.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Roncal C.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Calvayrac O.:
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain
Rodríguez C.:
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain
Varo N.:
Department of Biochemistry, University Clinic, University of Navarra, Pamplona, Spain
Purroy A.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Lorente L.:
Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
Rodríguez J.A.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Doeuvre L.:
INSERM, U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France
Hervás-Stubbs S.:
Laboratory of Immunology and Gene Therapy, Division of Gene Therapy and Hepatology, University of Navarra, Pamplona, Spain
Angles-Cano E.:
INSERM, U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France
Páramo J.A.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Hematology Service, University Clinic, University of Navarra, Pamplona, Spain
Martínez-González J.:
Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain
Orbe J.:
Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain
Bronze, All Open Access
|