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 rece...
| Autores: | ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artigo |
| Estado: | Published version |
| Data de publicação: | 2009 |
| País: | España |
| Recursos: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositório: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p12936 |
| Acesso em linha: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12936 |
| Nível de acesso: | Acesso aberto |
| Palavra-chave: | thrombin endothelium MMP-10 atherosclerosis thrombosis |
| _version_ | 1878741318225625088 |
|---|---|
| author | Orbe, J |
| author2 | Rodriguez, JA Calvayrac, O Rodriguez-Calvo, R Rodriguez, C Roncal, C de Lizarrondo, SM Barrenetxe, J Reverter, JC Martinez-Gonzalez, J Paramo, JA |
| author2_role | author author author author author author author author author author |
| author_browse | Barrenetxe, J Calvayrac, O Martinez-Gonzalez, J Orbe, J Paramo, JA Reverter, JC Rodriguez, C Rodriguez, JA Rodriguez-Calvo, R Roncal, C de Lizarrondo, SM |
| author_facet | Orbe, J Rodriguez, JA Calvayrac, O Rodriguez-Calvo, R Rodriguez, C Roncal, C de Lizarrondo, SM Barrenetxe, J Reverter, JC Martinez-Gonzalez, J Paramo, JA |
| author_role | author |
| collection | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| 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. (Arterioscler Thromb Vasc Biol. 2009;29:2109-2116.) |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_e30b521a9d8c1af7fa2f0ddd22cbc0a1 |
| institution | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| instname_str | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:iibsantpau.fundanetsuite.com:p12936 |
| publishDate | 2009 |
| publishDateSort | 2009 |
| publisher | LIPPINCOTT WILLIAMS & WILKINS |
| publisherStr | LIPPINCOTT WILLIAMS & WILKINS |
| reponame_str | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| spelling | Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation Orbe, J Rodriguez, JA Calvayrac, O Rodriguez-Calvo, R Rodriguez, C Roncal, C de Lizarrondo, SM Barrenetxe, J Reverter, JC Martinez-Gonzalez, J Paramo, JA thrombin endothelium MMP-10 atherosclerosis thrombosis 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. (Arterioscler Thromb Vasc Biol. 2009;29:2109-2116.) LIPPINCOTT WILLIAMS & WILKINS https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12936 |
| spellingShingle | Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation Orbe, J thrombin endothelium MMP-10 atherosclerosis thrombosis |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | thrombin endothelium MMP-10 atherosclerosis thrombosis |
| topic_facet | thrombin endothelium MMP-10 atherosclerosis thrombosis |
| url | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12936 |