Summary
Plasminogen activator inhibitor type-1 (PAI-1) can modify fibrinolytic activity in
vitro and in vivo. The present study was performed to determine whether pharmacologic
concentrations of tissue-typeplasminogen activator (t-PA) can initiate negative feedback
by stimulating PAI-1 synthesis. In both human hepatoma cells (Hep G2) and human umbilical
vein endothelial cells (HUVEC), t-PA increased the total concentrations and appearance
of newly synthesized protein inconditioned media of free PAI-1 and PAI-1 complexed
with t-PA in a dose and time dependent fashion judging from results after immunoprecipi-tation
of metabolically labeled PAI-1. The t-PA effect was not attributable simply to release
of stored or matrix-bound PAI-1. In HUVEC, Northern blot analyses indicated that t-PA
increased steady-state levels of PAI-1 mRNA two-fold. In contrast PAI-1 mRNA expression
was not increased in Hep G2 cells. Thus, mechanisms of stimulation appeared to differ
in the two cell lines. The results obtained are consistent with the hypothesis that
increased PAI-1 synthesis and secretion in response to t-PA may limit or attenuate
fibrinolysis locally or systemically in vivo.
