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

Abstract

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-alpha, inhibited basal and bFGF-stimulated PAI-1 expression. By inducing PAI-1 expression from ECs, bFGF may control proteolysis and fibrinolysis in vessel walls.

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

“…In the current study we observed an increase in F3 expression in the vessels of diabetic mice and have confirmed previous findings demonstrating the attenuation of F3 with fibrate treatment in endothelial cells [30], monocytes and macrophages [44].…”

“…Tissue factor has also been shown to be under the regulation of NF-κB [30] and be upregulated in diabetes, a state of increased thrombosis associated with plaque rupture [24]. In the current study we observed an increase in F3 expression in the vessels of diabetic mice and have confirmed previous findings demonstrating the attenuation of F3 with fibrate treatment in endothelial cells [30], monocytes and macrophages [44].…”

“…4a-d) demonstrate localisation of macrophages to the intima and media, which appear to be more pronounced in the diabetic mice compared with all other groups, consistent with enhanced Ccl2 expression. Tissue factor (F3) has also been demonstrated to be under the regulation of NF-κB [30]. Thus, we investigated …”

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…Also, FGFs modulate the expression of uPA receptor on the endothelial cell surface, thus allowing the localization of the proteolytic activity at the leading edge of the cell at the front of migration [22]. Furthermore, FGF1 and FGF2 induce the expression of the plasminogen activator inhibitor (PAI)-1 in cultured endothelial cells leading to a fine modulation of the proteolytic balance [23][24][25].…”

Shear stress‐induced Ets‐1 modulates protease inhibitor expression in microvascular endothelial cells

“…Aside from the established role of Ets-1 in regulating the expression of MMP-1, -3 and -9 (Sementchenko and Watson, 2000), it also has been reported that plasminogen activator inhibitor-1 is a target gene for Ets-1 (Kaneko et al, 2002). Similarly, the TIMP-1 promoter is activated by Ets-1 (Logan et al, 1996).…”