Open AccessHepatocyte Growth Factor Regulates E Box–Dependent Plasminogen Activator Inhibitor Type 1 Gene Expression in HepG2 Liver Cells
Author(s) -
Shogo Imagawa,
Satoshi Fujii,
Jie Dong,
Tomoo Furumoto,
Takeaki Kaneko,
Tarikuz Zaman,
Yuichi Satoh,
Hiroyuki Tsutsui,
Burton E. Sobel
Publication year - 2006
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/01.atv.0000240318.61359.e3
Subject(s) - hepatocyte growth factor , plasminogen activator inhibitor 1 , biology , microbiology and biotechnology , activator (genetics) , mapk/erk pathway , plasminogen activator , protein kinase a , kinase , tyrosine kinase , signal transduction , chemistry , endocrinology , biochemistry , gene , receptor
Objective— We sought to determine the etiologic mechanism of pleiotropic growth factor, hepatocyte growth factor (HGF), as a regulator of hepatic synthesis of plasminogen activator inhibitor (PAI)-1, the physiological inhibitor of fibrinolysis and a potential inducer of atherothrombosis.Methods and Results— HGF increased PAI-1 mRNA expression and PAI-1 protein accumulation in the conditioned media of human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. HGF-inducible PAI-1 mRNA was attenuated by U0126, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, and genistein, an inhibitor of tyrosine kinase. HGF increased the human PAI-1 promoter (−829 to +36 bp) activity, and deletion and mutation analysis uncovered a functional E box (5′-CACATG-3′) at positions −158 to −153 bp. Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways. Co-transfection of USF1 expression vector increased PAI-1 promoter activity. Sterol regulatory element-binding protein-1 attenuated HGF-inducible PAI-1 promoter activity.Conclusions— Because USFs are involved in the regulation of carbohydrates and lipid metabolism, HGF-mediated PAI-1 production may provide a novel link between atherothrombosis and metabolic derangements. Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients.