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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2407.)
© 2006 American Heart Association, Inc.

Thrombosis

Hepatocyte Growth Factor Regulates E Box–Dependent Plasminogen Activator Inhibitor Type 1 Gene Expression in HepG2 Liver Cells

Shogo Imagawa; Satoshi Fujii; Jie Dong; Tomoo Furumoto; Takeaki Kaneko; Tarikuz Zaman; Yuki Satoh; Hiroyuki Tsutsui; Burton E Sobel

From the Department of Cardiovascular Medicine (S.I., S.F., J.D., T.F., T.K., Y.S., H.T.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; Cardiovascular Research Institute (T.Z., B.E.S.), University of Vermont, Colchester, Vt.

Correspondence to Satoshi Fujii, MD, PhD, The Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kitaku, Sapporo, Japan 060-8638. E-mail sfujii{at}med.hokudai.ac.jp

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.

Hepatocyte growth factor increased PAI-1 mRNA expression and protein in highly differentiated human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. The increases were mediated by E box of the PAI-1 promoter. Targeting HGF pathway may modulate the thrombotic risk in high-risk patients.

Key Words: atherothrombosis • E box • hepatocyte growth factor • plasminogen activator inhibitors • promoters