Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation

Objective: thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. Methods and Results: thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated re...

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Autores: Orbe, Josune, Rodríguez, José Antonio, Calvayrac, Olivier, Rodríguez-Calvo, R., Rodríguez, C., Roncal Mancho, Carmen, Martínez de Lizarrondo, Sara, Barrenetxe, Jaione, Reverter, Juan Carlos, Martínez-González, José, Páramo, José A.
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2009
País:España
Recursos:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/56172
Acesso em linha:https://hdl.handle.net/2454/56172
Access Level:acceso abierto
Palavra-chave:Thrombin
Endothelium
MMP-10: Atherosclerosis
Thrombosis
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spelling Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generationOrbe, JosuneRodríguez, José AntonioCalvayrac, OlivierRodríguez-Calvo, R.Rodríguez, C.Roncal Mancho, CarmenMartínez de Lizarrondo, SaraBarrenetxe, JaioneReverter, Juan CarlosMartínez-González, JoséPáramo, José A.ThrombinEndotheliumMMP-10: AtherosclerosisThrombosisObjective: thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. Methods and Results: thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated receptor-1 (PAR-1)–dependent mechanism, in a dose- and time-dependent manner. This effect was mimicked by a PAR-1 agonist peptide (TRAP-1) and antagonized by an anti–PAR-1 blocking antibody. MMP-10 induction was dependent on extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways. By serial deletion analysis, site-directed mutagenesis and electrophoretic mobility shift assay an AP-1 site in the proximal region of MMP-10 promoter was found to be critical for thrombin-induced MMP-10 transcriptional activity. Thrombin and TRAP-1 upregulated MMP-10 in murine endothelial cells in culture and in vivo in mouse aorta. This effect of thrombin was not observed in PAR-1–deficient mice. Interestingly, circulating MMP-10 levels (P<0.01) were augmented in patients with endothelial activation associated with high (disseminated intravascular coagulation) and moderate (previous acute myocardial infarction) systemic thrombin generation. Conclusion: thrombin induces MMP-10 through a PAR-1–dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation.This work was funded through the 'UTE project CIMA' (University of Navarra), Ministerio de Sanidad y Consumo (FIS/PI050777 and FIS/PI061480), Ministerio de Educación y Ciencia (SAF2006-07378 and SAF2009-12039), Departamento de Salud, Gobierno de Navarra (39/2004), and Red Temática de Investigación Cardiovascular RECAVA (RD06/0014/0008 and RD06/0014/0027).American Heart AssociationCiencias de la SaludOsasun ZientziakGobierno de Navarra / Nafarroako Gobernua2009info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2454/56172reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/MSC//FIS%2FPI050777info:eu-repo/grantAgreement/MSC//FIS%2FPI061480info:eu-repo/grantAgreement/MEC//SAF2006-07378info:eu-repo/grantAgreement/MICINN//SAF2009-12039info:eu-repo/grantAgreement/Gobierno de Navarra//© 2009 Wolters Kluwer. This is a pre-copyedited, author-produced version of an article accepted for publication in Arteriosclerosis, Thrombosis, and Vascular Biology.info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/561722026-06-17T12:41:47Z
dc.title.none.fl_str_mv Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
title Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
spellingShingle Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
Orbe, Josune
Thrombin
Endothelium
MMP-10: Atherosclerosis
Thrombosis
title_short Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
title_full Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
title_fullStr Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
title_full_unstemmed Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
title_sort Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
dc.creator.none.fl_str_mv Orbe, Josune
Rodríguez, José Antonio
Calvayrac, Olivier
Rodríguez-Calvo, R.
Rodríguez, C.
Roncal Mancho, Carmen
Martínez de Lizarrondo, Sara
Barrenetxe, Jaione
Reverter, Juan Carlos
Martínez-González, José
Páramo, José A.
author Orbe, Josune
author_facet Orbe, Josune
Rodríguez, José Antonio
Calvayrac, Olivier
Rodríguez-Calvo, R.
Rodríguez, C.
Roncal Mancho, Carmen
Martínez de Lizarrondo, Sara
Barrenetxe, Jaione
Reverter, Juan Carlos
Martínez-González, José
Páramo, José A.
author_role author
author2 Rodríguez, José Antonio
Calvayrac, Olivier
Rodríguez-Calvo, R.
Rodríguez, C.
Roncal Mancho, Carmen
Martínez de Lizarrondo, Sara
Barrenetxe, Jaione
Reverter, Juan Carlos
Martínez-González, José
Páramo, José A.
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
Gobierno de Navarra / Nafarroako Gobernua
dc.subject.none.fl_str_mv Thrombin
Endothelium
MMP-10: Atherosclerosis
Thrombosis
topic Thrombin
Endothelium
MMP-10: Atherosclerosis
Thrombosis
description Objective: thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. Methods and Results: thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated receptor-1 (PAR-1)–dependent mechanism, in a dose- and time-dependent manner. This effect was mimicked by a PAR-1 agonist peptide (TRAP-1) and antagonized by an anti–PAR-1 blocking antibody. MMP-10 induction was dependent on extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways. By serial deletion analysis, site-directed mutagenesis and electrophoretic mobility shift assay an AP-1 site in the proximal region of MMP-10 promoter was found to be critical for thrombin-induced MMP-10 transcriptional activity. Thrombin and TRAP-1 upregulated MMP-10 in murine endothelial cells in culture and in vivo in mouse aorta. This effect of thrombin was not observed in PAR-1–deficient mice. Interestingly, circulating MMP-10 levels (P<0.01) were augmented in patients with endothelial activation associated with high (disseminated intravascular coagulation) and moderate (previous acute myocardial infarction) systemic thrombin generation. Conclusion: thrombin induces MMP-10 through a PAR-1–dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation.
publishDate 2009
dc.date.none.fl_str_mv 2009
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/56172
url https://hdl.handle.net/2454/56172
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MSC//FIS%2FPI050777
info:eu-repo/grantAgreement/MSC//FIS%2FPI061480
info:eu-repo/grantAgreement/MEC//SAF2006-07378
info:eu-repo/grantAgreement/MICINN//SAF2009-12039
info:eu-repo/grantAgreement/Gobierno de Navarra//
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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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