Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 29, Issue 12, Pages 2109-U289Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.194589
Keywords
thrombin; endothelium; MMP-10; atherosclerosis; thrombosis
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Funding
- UTE project CIMA (University of Navarra)
- Ministerio de Sanidad y Consumo [FIS/PI050777, FIS/PI061480]
- Ministerio de Educacion y Ciencia [SAF2006-07378, SAF2009-12039]
- Departamento de Salud, Gobierno de Navarra [39/2004]
- Red Tematica de Investigacion Cardiovascular RECAVA [RD06/0014/0008, RD06/0014/0027]
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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.)
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