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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:855.)
© 2002 American Heart Association, Inc.

Thrombosis

Induction of Plasminogen Activator Inhibitor-1 in Endothelial Cells by Basic Fibroblast Growth Factor and Its Modulation by Fibric Acid

Takeaki Kaneko; Satoshi Fujii; Akio Matsumoto; Daisuke Goto; Naoki Ishimori; Keiko Watano; Tomoo Furumoto; Taeko Sugawara; Burton E. Sobel; Akira Kitabatake

From the Department of Cardiovascular Medicine (T.K., S.F., D.G., N.I., K.W., T.F., T.S., A.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; the Howard Hughes Medical Institute (A.M.), Duke University, Durham, NC; and the Department of Medicine (B.E.S.), University of Vermont, Burlington.

Correspondence to Satoshi Fujii, MD, PhD, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638. E-mail sfujii@ med.hokudai.ac.jp

Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis and proteolysis. Basic fibroblast growth factor (bFGF) stimulates angiogenesis, which requires regional proteolysis. Because modulation of vasculopathy requires tight control of proteolysis, effects of bFGF on PAI-1 expression in endothelial cells (ECs) were characterized. bFGF increased PAI-1 mRNA and accumulation of PAI-1 protein in conditioned media in human umbilical vein ECs. The bFGF-mediated increase in PAI-1 mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. The rate of decrease in PAI-1 mRNA after actinomycin D treatment was not affected by bFGF. Transient transfection assays of the human PAI-1 promoter-luciferase construct demonstrated that bFGF-induced PAI-1 transcription was dependent on the elements within the -313 to -260 bp relative to the transcription start site. This region contains an E26 transformation specific 1 (Ets-1)-like site. Electrophoretic mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of the Ets-1-like transcription factor to the PAI-1 promoter. Nucleotide substitution to disrupt the Ets-1-like site reduced bFGF-stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator-activated receptor-, inhibited basal and bFGF-stimulated PAI-1 expression. By inducing PAI-1 expression from ECs, bFGF may control proteolysis and fibrinolysis in vessel walls.

Key Words: endothelium • basic fibroblast growth factors • plasminogen activator inhibitors • promoters • fibric acid

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