Stimulation by retinoids of tissue-type plasminogen activator secretion in cultured human endothelial cells: relations of structure to effect.
Retinoic acid induces tissue-type plasminogen activator (t-PA) but not plasminogen activator inhibitor-1 (PAI-1) expression in cultured human umbilical vein endothelial cells (HUVEC). To further investigate the relation between the structure of the retinoids and their ability to induce t-PA synthesis in vitro, 11 analogues were studied in HUVEC culture. The retinoid analogues were classified into one of three groups according to their t-PA-inducing potential. Group 1 showed little induction (0.9- to 1.9-fold after 48 h) at concentrations between 10(-8) and 10(-6) M. Group 2, which includes all-trans-retinoic acid, induced t-PA threefold to fivefold at 10(-6) M but had little effect at 10(-8) M (less than threefold). Group 3, which comprises arotinoid acid (RO-13-7410) and RO-13-6307, induced t-PA antigen secretion fivefold at 10(-8) M. The retinoids of groups 2 and 3 had a terminal carboxyl group and alkyl substitution of the lipophylic head of the retinoid skeleton. The group 3 retinoids also contained an aromatic ring. The t-PA-inducing activity of these third-generation retinoids correlates to some extent with other activities, including regression of papilloma, keratinization in vivo, and clonal inhibition of tumor cell lines in vitro. Some of the retinoids caused a small but significant (up to 1.5-fold at 24 h) increase in PAI-1 antigen secretion. The group 3 retinoids appear to be sufficiently potent inducers of t-PA secretion to warrant further investigation in in vivo animal models.
Bulens
F
F
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Nelles
L
L
Van den Panhuyzen
N
N
Collen
D
D
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015849:Plasminogen Inactivators / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000378:metabolism; D014471:Umbilical Veins
D015849:Plasminogen Inactivators; D012176:Retinoids; D010959:Tissue Plasminogen Activator