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...

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Autores: Martínez de Lizarrondo, Sara, Roncal Mancho, Carmen, Calvayrac, Olivier, Rodríguez, Cristina, Varo, Nerea, Purroy, Ana, Lorente, Leonardo, Rodríguez, José Antonio, Doeuvre, Loïc, Hervás Stubbs, Sandra, Anglés-Cano, Eduardo, Páramo, José A., Martínez-González, José, Orbe, Josune
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/56170
Acceso en línea:https://hdl.handle.net/2454/56170
Access Level:acceso abierto
Palabra clave:Matrix metalloproteinase-10
Endothelium
Thrombin
CD40 ligand
Microparticles
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spelling Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivoMartínez de Lizarrondo, SaraRoncal Mancho, CarmenCalvayrac, OlivierRodríguez, CristinaVaro, NereaPurroy, AnaLorente, LeonardoRodríguez, José AntonioDoeuvre, LoïcHervás Stubbs, SandraAnglés-Cano, EduardoPáramo, José A.Martínez-González, JoséOrbe, JosuneMatrix metalloproteinase-10EndotheliumThrombinCD40 ligandMicroparticlesObjective—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, α-CD40L, and α-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.This work was funded through the "UTE project CIMA" (Universityof Navarra) and grants SAF2009-11949, SAF2009-12039 from Ministerio de Ciencia e Innovación (MICINN), and Red Temáticade Investigación Cardiovascular RECAVA (RD06/0014/0008 andRD06/0014/0027) and FIS/PS09/00143, FIS/PI-10-01572, and I3SNS-INT-11-063 from Instituto de Salud Carlos III (Madrid, Spain). Sara Martínez de Lizarrondo and Ana Purroy were sup-ported by a fellowship from the Education Department, Gobierno de Navarra. Carmen Roncal was supported by the Ministry of Scienceand Innovation MICINN-PTQ -09-02-01941.American Heart AssociationCiencias de la SaludOsasun Zientziak2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2454/56170reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/MICINN//SAF2009-11949info:eu-repo/grantAgreement/MICINN//SAF2009-12039info:eu-repo/grantAgreement/MICINN//PS09%2F00143info:eu-repo/grantAgreement/ISCIII//PI-10-01572info:eu-repo/grantAgreement/ISCIII//I3SNS-INT-11-063info:eu-repo/grantAgreement/MICINN//PTQ-09-02-01941© 2012 American Heart Association, Inc.info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/561702026-06-17T12:41:47Z
dc.title.none.fl_str_mv Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
title Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
spellingShingle Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
Martínez de Lizarrondo, Sara
Matrix metalloproteinase-10
Endothelium
Thrombin
CD40 ligand
Microparticles
title_short Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
title_full Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
title_fullStr Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
title_full_unstemmed Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
title_sort Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo
dc.creator.none.fl_str_mv Martínez de Lizarrondo, Sara
Roncal Mancho, Carmen
Calvayrac, Olivier
Rodríguez, Cristina
Varo, Nerea
Purroy, Ana
Lorente, Leonardo
Rodríguez, José Antonio
Doeuvre, Loïc
Hervás Stubbs, Sandra
Anglés-Cano, Eduardo
Páramo, José A.
Martínez-González, José
Orbe, Josune
author Martínez de Lizarrondo, Sara
author_facet Martínez de Lizarrondo, Sara
Roncal Mancho, Carmen
Calvayrac, Olivier
Rodríguez, Cristina
Varo, Nerea
Purroy, Ana
Lorente, Leonardo
Rodríguez, José Antonio
Doeuvre, Loïc
Hervás Stubbs, Sandra
Anglés-Cano, Eduardo
Páramo, José A.
Martínez-González, José
Orbe, Josune
author_role author
author2 Roncal Mancho, Carmen
Calvayrac, Olivier
Rodríguez, Cristina
Varo, Nerea
Purroy, Ana
Lorente, Leonardo
Rodríguez, José Antonio
Doeuvre, Loïc
Hervás Stubbs, Sandra
Anglés-Cano, Eduardo
Páramo, José A.
Martínez-González, José
Orbe, Josune
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
dc.subject.none.fl_str_mv Matrix metalloproteinase-10
Endothelium
Thrombin
CD40 ligand
Microparticles
topic Matrix metalloproteinase-10
Endothelium
Thrombin
CD40 ligand
Microparticles
description 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, α-CD40L, and α-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.
publishDate 2012
dc.date.none.fl_str_mv 2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/56170
url https://hdl.handle.net/2454/56170
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN//SAF2009-11949
info:eu-repo/grantAgreement/MICINN//SAF2009-12039
info:eu-repo/grantAgreement/MICINN//PS09%2F00143
info:eu-repo/grantAgreement/ISCIII//PI-10-01572
info:eu-repo/grantAgreement/ISCIII//I3SNS-INT-11-063
info:eu-repo/grantAgreement/MICINN//PTQ-09-02-01941
dc.rights.none.fl_str_mv © 2012 American Heart Association, Inc.
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © 2012 American Heart Association, Inc.
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Heart Association
publisher.none.fl_str_mv American Heart Association
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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