title: Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes.
abstract: Thrombin plays an important role in diverse neurological processes such as proliferation, cell migration, differentiation and neuroinflammation. In this study, we investigated the effect of thrombin on matrix metalloprotease-9 (MMP-9) expression in rat primary astrocytes. Thrombin (1-10U/ml) induced a significant increase in MMP-9 activity as measured by gelatin zymography. Thrombin also increased MMP-9 mRNA expression. Among three isotypes of thrombin receptor, i.e. protease-activated receptor (PAR)-1, -3 and -4, PAR1 agonist (1-100muM) but not PAR3 and PAR4 agonist induced MMP-9 expression. Inhibition of thrombin-induced MMP-9 production by SCH 79797 (10-50nM), a selective PAR1 receptor antagonist, confirmed that PAR1 is a main receptor for thrombin-induced MMP-9 expression. In astrocytes, thrombin activated Erk1/2, and it was inhibited by PD98059. In this study, thrombin-induced MMP-9 expression was inhibited by PD98059. PAR1 agonist activated Erk1/2 and PD98059 inhibited PAR1 agonist-induced MMP-9 expression. MMP-9 promoter reporter assay confirmed the positive effect of ERK1/2 on MMP-9 expression. These results suggest that the activation of PAR1 mediates thrombin-induced MMP-9 expression through the regulation of Erk1/2.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Min Sik
authors.initials: MS
authors.lastname: Choi
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kim
authors.forename: Woo Jong
authors.initials: WJ
authors.lastname: Lee
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Choi
authors.forename: Gyu Hwan
authors.initials: GH
authors.lastname: Park
authors.forename: Sun Don
authors.initials: SD
authors.lastname: Kim
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jeon
authors.forename: Hyo Sang
authors.initials: HS
authors.lastname: Go
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Shin
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: Ko
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D010975:Platelet Aggregation Inhibitors