Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation
Por:
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
Publicada:
1 dic 2009
Resumen:
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.)
Filiaciones:
Orbe, J:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Rodriguez, JA:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Calvayrac, O:
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Ctr Invest Cardiovasc, Barcelona, Spain
Rodriguez-Calvo, R:
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Ctr Invest Cardiovasc, Barcelona, Spain
Rodriguez, C:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Roncal, C:
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Ctr Invest Cardiovasc, Barcelona, Spain
de Lizarrondo, SM:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Barrenetxe, J:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Reverter, JC:
Univ Barcelona, Hosp Clin, Dept Haemotherapy & Haemostasis, E-08007 Barcelona, Spain
Martinez-Gonzalez, J:
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Ctr Invest Cardiovasc, Barcelona, Spain
Paramo, JA:
Univ Navarra, Atherothrombosis Res Lab, Div Cardiovasc Dis, Ctr Appl Med Res,CIMA, E-31080 Pamplona, Spain
Univ Navarra, Univ Clin, Hematol Serv, E-31080 Pamplona, Spain
Bronze, Green Published
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