title: Thrombin regulates matrix metalloproteinase-9 expression in human monocytes.
abstract: We investigated whether thrombin, the final activator of coagulation cascade, regulates expression of matrix metalloproteinases (MMP)-9 in human monocytes. We show that thrombin stimulation induced MMP-9 secretion of monocytes dose- and time-dependently as revealed by gelatin zymography. Real-time RT-PCR and Western blot analysis demonstrated that thrombin up-regulated mRNA and protein levels of MMP-9. Pre-incubation with anti-protease-activated receptor (PAR)-1 or anti-PAR-3 antibody partially inhibited the thrombin-induced MMP-9 secretion. Simultaneous incubation with both showed synergistic effect, indicating the involvement of both receptors in this thrombin effect. BAPTA, a Ca(2+) chelator, abolished the thrombin-induced MMP-9 secretion, indicating the requirement of Ca(2+) mobilization in this process. Inhibition of thrombin-induced MMP-9 secretion by either MEK inhibitor or p38 kinase inhibitor revealed that the thrombin effect was mediated by both ERK1/2 and p38 pathways. The activation of NFkappaB by thrombin as demonstrated by electromobility shift assay was also shown to be critical to the thrombin-induced MMP-9 up-regulation.
authors.affiliation: The First Cardiovascular Division, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Chi-Jen
authors.initials: CJ
authors.lastname: Chang
authors.forename: Lung-An
authors.initials: LA
authors.lastname: Hsu
authors.forename: Yu-Hsein
authors.initials: YH
authors.lastname: Ko
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chen
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chuang
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Liao
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
mesh_terms: D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D019715:Tissue Inhibitor of Metalloproteinase-1; C105295:protease-activated receptor 3; D004533:Egtazic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D020780:Matrix Metalloproteinase 9; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium