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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Ciencias Cardiovasculares > Aterosclerosis e inflamación > DA - CIMA - Cardiovasculares - Aterosclerosis e inflamación - Artículos de revista >

Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation
Authors: Orbe, J. (Josune)
Rodriguez, J.A. (José Antonio)
Calvayraz, O. (Olivier)
Rodriguez-Calvo, R. (Ricardo)
Rodriguez, C. (Cristina)
Roncal, C. (Carmen)
Martinez-de-Lizarrondo, S. (Sara)
Barrenetxe, J. (Jaione)
Reverter, J.C. (Juan C.)
Martinez-Gonzalez, J. (José)
Paramo, J.A. (José Antonio)
Keywords: Thrombin
Endothelium
MMP-10
Atherosclerosis
Thrombosis
Issue Date: 2009
Publisher: American Heart Association
Publisher version: http://atvb.ahajournals.org/content/29/12/2109
ISSN: 1524-4636
Citation: Orbe J, Rodriguez JA, Calvayrac O, Rodriguez-Calvo R, Rodriguez C, Roncal C, et al. Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation. Arterioscler Thromb Vasc Biol 2009 Dec;29(12):2109-2116.
Abstract
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. CONCLUSIONS: 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.
Permanent link: http://hdl.handle.net/10171/22257
Appears in Collections:DA - CIMA - Cardiovasculares - Aterosclerosis e inflamación - Artículos de revista

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