Genistein reduces tumor necrosis factor α-induced plasminogen activator inhibitor-1 transcription but not urokinase expression in human endothelial cells
| Autor: | Hinsbergh, V.W.M. van, Vermeer, M., Koolwijk, P., Grimbergen, J., Kooistra, T. |
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| Přispěvatelé: | Gaubius Laboratory TNO Preventie en Gezondheid |
| Jazyk: | angličtina |
| Rok vydání: | 1994 |
| Předmět: |
cell migration
plasminogen activator urokinase protein tyrosine phosphatase Receptors Tumor Necrosis Factor genistein bacterium lipopolysaccharide Protein-Tyrosine Kinase Plasminogen Activator Inhibitor 1 endothelium cell vanadic acid mitogenesis Support Non-U.S. Gov't enzyme inhibition transcription factor Cells Cultured tumor necrosis factor alpha plasminogen activation human cell genetic transcription herbimycin a enzyme activation Isoflavones In Vitro priority journal Health Tissue Plasminogen Activator Urinary Plasminogen Activator fibrinolysis Fibroblast Growth Factor 2 Endothelium Vascular daidzein tyrphostin Tumor Necrosis Factor signal transduction Human |
| Zdroj: | Blood, 9, 84, 2984-2991 |
| Popis: | The plasminogen activator inhibitor PAI-1 is markedly elevated in vivo and in vitro upon exposure to the inflammatory mediators tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and bacterial lipopolysaccharide. Here we report that the isoflavone compound genistein prevents the increase in synthesis of PAI-1 induced by these inflammatory mediators in human endothelial cells in vitro, and partially reduces the basal PAI-1 production by these cells. These effects of genistein were accompanied by a decrease in PAI-1 mRNA and in a suppression of the PAI-1 transcription rate as shown by run-on assay. A specific action of genistein, probably by inhibiting a tyrosine protein kinase, is likely, because the structural genistein analogue daidzein, which has a low tyrosine protein kinase inhibitor activity, did not inhibit PAI-1 synthesis. Vanadate, a tyrosine protein phosphatase inhibitor, increased PAI-1 production. The effect of genistein on PAI-1 synthesis was rather selective. Herbimycin A also reduced PAI-1 synthesis, but several other tyrosine protein kinase inhibitors, namely tyrphostin A47, methyl-2,5- dihydroxy-cinnamate, and compound 5, were unable to do so. All these tyrosine protein kinase inhibitors reduced basic fibroblast growth factor (b-FGF)- induced [3H]thymidine incorporation in endothelial cells. This indicates that the effect of genistein on PAI-1 transcription proceeds independently of its effect on mitogenesis. In contrast to TNFα-induced PAI-1 production, the transcription and synthesis of urokinase-type plasminogen activator (u-PA) was not inhibited by genistein. A TNFα-mutant (Trp12Thr36TNFα) that specifically recognizes the 55-kD TNF-receptor, mimicked the effects of TNFα on both PAI-1 and u-PA. Because genistein affected PAI-1, but not u-PA induced by this mutant, involvement of different TNF-receptors cannot underlie the difference in the effects of genistein on PAI-1 and u-PA synthesis. Because genistein also inhibited PAI-1 induction by thrombin and IL-4, it is likely that genistein does not act on a TNFα-receptor-coupled protein kinase but on the signal transduction pathway enhancing PAI-1 transcription. Our results suggest that the TNFα-induced signal transduction pathway of PAI-1 transcription involves a genistein-sensitive step that is not involved in the induction of u-PA by TNFα. Given the limited sensitivity to several other tyrosine protein kinase inhibitors, this genistein- sensitive step may be a potential target for pharmacologic intervention to reduce elevated plasma PAI-1 levels. Chemicals/CAS: Fibroblast Growth Factor 2, 103107-01-3; Genistein, 446-72-0; Isoflavones; Plasminogen Activator Inhibitor 1; Protein-Tyrosine Kinase, EC 2.7.1.112; Receptors, Tumor Necrosis Factor; Tissue Plasminogen Activator, EC 3.4.21.68; Tumor Necrosis Factor; Urinary Plasminogen Activator, EC 3.4.21.73 |
| Databáze: | OpenAIRE |
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