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Genistein reduces tumor necrosis factor alpha-induced plasminogen activator
inhibitor-1 transcription but not urokinase expression in human endothelial
cells
VW van Hinsbergh, M Vermeer, P Koolwijk, J Grimbergen and T Kooistra
Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
The plasminogen activator inhibitor PAI-1 is markedly elevated in vivo and
in vitro upon exposure to the inflammatory mediators tumor necrosis factor
alpha (TNF alpha), 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 TNF-alpha-induced PAI-1 production,
the transcription and synthesis of urokinase-type plasminogen activator
(u-PA) was not inhibited by genistein. A TNF- alpha-mutant (Trp32Thr86TNF
alpha) that specifically recognizes the 55- kD TNF-receptor, mimicked the
effects of TNF alpha 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 TNF
alpha-receptor- coupled protein kinase but on the signal transduction
pathway enhancing PAI-1 transcription. Our results suggest that the TNF
alpha-induced signal transduction pathway of PAI-1 transcription involves a
genistein- sensitive step that is not involved in the induction of u-PA by
TNF alpha. 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.
Volume 84,
Issue 9,
pp. 2984-2991,
11/01/1994
Copyright © 1994 by The American Society of Hematology
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