Heparin stimulates fibrinolysis in mesothelial cells by selective induction of tissue-plasminogen activator but not plasminogen activator inhibitor-1 synthesis.
The regulation of tissue-plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) synthesis was studied in cultured human mesothelial cells derived from omentum (HOMC). Heparin (100 U/ml) as well as pentosan polysulfate (300 micrograms/ml) stimulated tPA synthesis by HOMC 2.9-4.5-fold. Heparin-induced tPA production was dose- and time-dependent and was inhibited by cycloheximide. tPA production by HOMC was also stimulated by phorbol 12-myristate 13-acetate (2.6-fold), fibrin clots (1.9-fold), or batroxobin (1.9-fold). Heparin and pentosan polysulfate did not stimulate PAI-1 production by HOMC, while phorbol 12-myristate 13-acetate (100 nM) increased the concentration of PAI-1 in the conditioned medium by 2.6-fold over 24 h. The interaction of heparin with HOMC was studied by direct binding experiments. Dose-dependent specific binding of biotinylated heparin to HOMC was saturable at about 10 micrograms/ml, the KD was estimated to about 0.15 microM. Biotinylated heparin bound rapidly to HOMC and reached a plateau within 60 min. Unlabeled heparin as well as pentosan polysulfate inhibited binding of biotinylated heparin in a dose-dependent fashion. These data demonstrate that heparin interacts with HOMC, and increases the fibrinolytic capacity in these cells by selectively increasing the production of tPA.
Grulich-Henn
J
J
Max-Planck-Gesellschaft, Clinical Research Unit for Blood Coagulation and Thrombosis, Giessen, Federal Republic of Germany.
Preissner
K T
KT
Müller-Berghaus
G
G
D001710:Biotin; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000494:pharmacology; D006801:Humans; D009852:Omentum; D015849:Plasminogen Inactivators / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*
D006494:Heparin Antagonists; D015849:Plasminogen Inactivators; D003609:Dactinomycin; D001710:Biotin; D006493:Heparin; D003513:Cycloheximide; D010959:Tissue Plasminogen Activator