Inhibitory effect of a new butadiene derivative on the production of plasminogen activator inhibitor-1 in cultured bovine endothelial cells.
Tissue-type plasminogen activator (t-PA) and its physiological inhibitor, plasminogen activator inhibitor-1 (PAI-1), are known to be synthesized by vascular endothelial cells and to play important roles in regulating the fibrinolytic activity of plasma. We found that a new butadiene derivative, (3E, 4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)pyrrolidine -2,5-dione (T-686), inhibits PAI-1 production without affecting plasminogen activator (PA) synthesis in cultured bovine endothelial cells. T-686 (1-10 microM) dose-dependently decreased the accumulation of PAI-1 in conditioned medium from the treated cells and elevated PA activity in the conditioned medium. Analysis of the conditioned medium by the zymography technique indicated that T-686 decreased the activities of PAI-1 with an M(r) of 55,000 and t-PA/PAI-1 complex with an M(r) of 99,000. Furthermore, T-686 attenuated the augmentation of PAI-1 antigen induced by lipopolysaccharide in the conditioned medium. The decrease of PAI-1 antigen was in parallel with the reduction of the PAI-1 mRNA level (Northern blots). These results suggest that T-686 can promote net fibrinolytic activity through suppression of PAI-1 production without affecting PA elaboration in endothelial cells.
Ohtani
A
A
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama.
Takagi
T
T
Hirano
A
A
Murakami
J
J
Sasaki
Y
Y
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002070:Butadienes / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005342:Fibrinolysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008970:Molecular Weight; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D013388:Succinimides / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D001597:Benzylidene Compounds; D002070:Butadienes; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013388:Succinimides; C104988:T 686; D010959:Tissue Plasminogen Activator