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.


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.
Orbe
Josune
J
Atherothrombosis Research Laboratory, Division of Cardiovascular Science, Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain.
Rodríguez
José A
JA
Calvayrac
Olivier
O
Rodríguez-Calvo
Ricardo
R
Rodríguez
Cristina
C
Roncal
Carmen
C
Martínez de Lizarrondo
Sara
S
Barrenetxe
Jaione
J
Reverter
Juan C
JC
Martínez-González
José
J
Páramo
José A
JA
D000818:Animals; D016022:Case-Control Studies; D002417:Cattle; D002478:Cells, Cultured; D004211:Disseminated Intravascular Coagulation / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D020935:MAP Kinase Signaling System; D053506:Matrix Metalloproteinase 10 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis* / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D044463:Receptor, PAR-1; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D013917:Thrombin; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10