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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2407-2413
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number10
DOIs
Publication statusPublished - Oct 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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