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 inhibit or, plasminogen activator inhibitor-1 (PAI-1), are known to be synthes ized by vascular endothelial cells and to play important roles in regu lating the fibrinolytic activity of plasma, We found that a new butadi ene derivative, (3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione (T- 686), inhibits PAI-1 production without affecting plasminogen activato r (PA) synthesis in cultured bovine endothelial cells, T-688 (1-10 mu M) dose-dependently decreased the accumulation of PAI-I in conditioned medium from the treated cells and elevated PA activity in the conditi oned medium, Analysis of the conditioned medium by the zymography tech nique 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, Furthermo re, T-686 attenuated the augmentation of PAI-1 antigen induced by lipo polysaccharide in the conditioned medium, The decrease of PAI-1 antige n 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.