Stimulation of tissue-type plasminogen activator synthesis by retinoids in cultured human endothelial cells and rat tissues in vivo.
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 microM) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kooistra
T
T
Gaubius Institute TNO, Leiden, The Netherlands.
Opdenberg
J P
JP
Toet
K
K
Hendriks
H F
HF
van den Hoogen
R M
RM
Emeis
J J
JJ
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002478:Cells, Cultured; D015342:DNA Probes; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D015849:Plasminogen Inactivators / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D012176:Retinoids / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control; D014020:Tissue Extracts; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*; D014802:Vitamin A Deficiency / Q000378:metabolism
D002087:Butyrates; D015342:DNA Probes; D015849:Plasminogen Inactivators; D012176:Retinoids; D014020:Tissue Extracts; D020148:Butyric Acid; D011493:Protein Kinase C; D010959:Tissue Plasminogen Activator