Summary
Increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in plasma
are associated with impaired fibrinolysis and venous and arterial thrombo-embolic
disease. In pilot studies designed to identify pharmacologic approaches capable of
diminishing such increases, we found that gemfibrozil attenuated the Stimulation of
synthesis of PAI-1 in a human, immortal, hepatoma cell line (Hep G2) induced by platelets.
The present study was performed to determine whether it exerts analogous effects in
non-immortal endothelial cells and whether it may therefore facilitate fibrinolysis
locally in vivo. Human umbilical vein endothelial cells were incubated with pharmacologic
concentrations of gemfibrozil. Gemfibrozil, 100 μM, suppressed basal PAI-1 production
by 15% and attenuated the augmentation of synthesis of PAI-1 induced by lysates from
platelets (4 × 107/ml) by 36% over 24 h without inhibiting overall protein synthesis. In addition, the
increases in PAI-1 mRNA otherwise induced by platelet lysates over 6 h were suppressed
by 49% (Northern blots) without any demonstrable change in the intracellular half-life
of PAI-1 mRNA. Pulse-chase experiments demonstrated diminution of PAI-1 protein synthesis
in parallel with the changes observed in PAI-1 mRNA. To determine whether these effects
of gemfibrozil on endothelial cells in vitro were paralleled by consistent changes
in the concentrations of PAI-1 in plasma in vivo, we studied rabbits with induced
carotid artery thrombosis and thrombolysis. The increases in plasma PAI-1 induced
by thrombosis and thrombolysis were inhibited by gemfibrozil (8.75 mg/kg i.v.), by
14% and 75%, respectively, Increases in endothelial cell PAI-1 gene expression in
aorta, liver, and heart (4–6 fold over control) induced by thrombolysis were attenuated
by gemfibrozil as well. Thus, gemfibrozil can attenuate shut down of the fibrinolytic
system that is known to accompany thrombosis and thrombolysis and may therefore diminish
the likelihood of early, thrombotic coronary artery reocclusion following revascularization
with fibrinolytic agents.
