Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
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/m...
| Autores: | , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2012 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p10467 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10467 https://www.scopus.com/inward/record.uri?eid=2-s2.0-84861529113&doi=10.1161%2fATVBAHA.112.248773&partnerID=40&md5=b2c680a78119daa02281671ac1b2415d |
| Access Level: | acceso abierto |
| Palabra clave: | CD40 ligand hirudin lipopolysaccharide messenger RNA mitogen activated protein kinase p38 proteinase activated receptor 1 stress activated protein kinase 1 stromelysin 2 thrombin animal experiment animal model article controlled study endothelial microparticle endothelium cell human human cell human tissue in vitro study in vivo study major clinical study male mouse nonhuman priority journal protein expression thrombosis Adult Aged Aged, 80 and over Animals Antibodies Antigens, CD40 Blood Coagulation Case-Control Studies CD40 Ligand Cell-Derived Microparticles Cells, Cultured Disease Models, Animal Disseminated Intravascular Coagulation Endothelial Cells Endotoxemia Female Gene Expression Regulation, Enzymologic Hirudins Human Umbilical Vein Endothelial Cells Humans Lipopolysaccharides Male Matrix Metalloproteinase 10 Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Mitogen-Activated Protein Kinase 8 Multivariate Analysis p38 Mi |
| Sumario: | 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. |
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