Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes.
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.
Choi
Min Sik
MS
Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Kim
Young Eun
YE
Lee
Woo Jong
WJ
Choi
Ji Woong
JW
Park
Gyu Hwan
GH
Kim
Sun Don
SD
Jeon
Se Jin
SJ
Go
Hyo Sang
HS
Shin
Sun Mi
SM
Kim
Won-Ki
WK
Shin
Chan Young
CY
Ko
Kwang Ho
KH
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
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