Stimulation of Tissue-Type Plasminogen Activator Synthesis by Retinoids in Cultured Human Endothelial Cells and Rat Tissues In Vivo

Abstract

SummaryTissue-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.