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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2109.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation

Josune Orbe; José A. Rodríguez; Olivier Calvayrac; Ricardo Rodríguez-Calvo; Cristina Rodríguez; Carmen Roncal; Sara Martínez de Lizarrondo; Jaione Barrenetxe; Juan C. Reverter; José Martínez-González; José A. Páramo

From the Atherothrombosis Research Laboratory, Division of Cardiovascular Sciences (J.O., J.A.R., C.R., S.M.d.L., J.B., J.A.P.), Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain; Centro de Investigación Cardiovascular (CSIC-ICCC) (O.C., R.R.-C., C.R., J.M.-G.), Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; the Department of Haemotherapy and Haemostasis (J.C.R.), Hospital Clinic, University of Barcelona, Spain; and the Hematology Service (J.A.P.), University Clinic, University of Navarra, Pamplona, Spain.

Correspondence to José A. Páramo, Atherothrombosis Research Laboratory, Division of Cardiovascular Science, CIMA-University of Navarra, Avda. Pio XII, 55 31008 Pamplona, Navarra, Spain. E-mail japaramo{at}unav.es José Martínez-González, Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu I Sant Pau, Sant Antoni M^a Claret 167, 08025 Barcelona, Spain. E-mail jmartinez@csic-iccc.org.

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.

Thrombin can interact with extracellular matrix components and promote vascular proinflammatory responses including MMP upregulation. We show that thrombin induces endothelial MMP-10, in vitro and in vivo, through a PAR-1–dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Increased MMP-10 can be observed in pathologies with augmented thrombin generation.

Key Words: thrombin • endothelium • MMP-10 • atherosclerosis • thrombosis