Summary
Tissue-type plasminogen activator (t-PA) and its inhibitor, plasminogen activator
inhibitor 1 (PAI-1), play an important role in regulating the fibrinolytic capacity
of plasma. Both t-PA and PAI-1 are synthesized by the endothelium. We report that
retinoic acid (vitamin A acid) and other retinoids rather specifically stimulate the
production of t-PA by cultured human umbilical vein endothelial cells. Effective retinoids
induced a dose-dependent (range: 0.01-50 μM) increase in the production of t-PA of
maximally about six-fold, while simultaneously causing no or only a small increase
(less than two-fold) of PAI-1. The effects on t-PA synthesis were apparent by 4-8
h, and reached maximal values after about 24-48 h of incubation with retinoid. The
retinoid effect on t-PA production was accompanied by increased t-PA mRNA levels,
without any parallel change in PAI-1 or GAPDH mRNA concentrations. The study also
shows that modifications at the carboxyl group of retinoic acid are associated with
a decrease in stimulatory potency. The stimulatory pathway appears to be identical
for all retinoids but distinct from a pathway by which another strong inducer, sodium
butyrate, induces t-PA synthesis in endothelial cells. The induction of t-PA by retinoids
might involve protein kinase C (PKC) as judged by an experiment using a specific PKC
inhibitor.
The effect of retinoids on the fibrinolytic system in vivo was assessed by feeding
rats with a vitamin A deficient diet or a diet with excess of vitamin A or other retinoids.
The activity and antigen levels for t-PA in plasma and tissue samples were strongly
decreased in vitamin A-starved animals, and enhanced in retinoid-fed animals. The
recognition of a class of compounds, the retinoids, that can increase t-PA synthesis
in cultured human endothelial cells and in rat tissues in vivo, may be of importance
in designing an effective method to enhance plasma fibrinolytic activity, and thereby
in preventing thrombotic phenomena.
