Induction of plasminogen activator inhibitor-1 in endothelial cells by basic fibroblast growth factor and its modulation by fibric acid.
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.
Kaneko
Takeaki
T
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Fujii
Satoshi
S
Matsumoto
Akio
A
Goto
Daisuke
D
Ishimori
Naoki
N
Watano
Keiko
K
Furumoto
Tomoo
T
Sugawara
Taeko
T
Sobel
Burton E
BE
Kitabatake
Akira
A
D024506:5' Flanking Region / Q000235:genetics; D000924:Anticholesteremic Agents / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D004247:DNA / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017395:Plasminogen Activator Inhibitor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D003609:Dactinomycin; D004247:DNA; C006012:fenofibric acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D011345:Fenofibrate