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Synergistic induction of plasminogen activator inhibitor type-1 in HEP G2
cells by thrombin and transforming growth factor-beta
WE Hopkins, S Fujii and BE Sobel
Cardiovascular Division, Washington University School of Medicine, St
Louis, MO 63110.
Plasminogen activator inhibitor type-1 (PAI-1) is a physiologic modulator
of the fibrinolytic system. Its activity in plasma increases in diverse
thrombotic states. The large synthetic capacity of the liver make it a
source of potentially large amounts of PAI-1. Because thrombin activity
increases in association with thrombotic disorders and because specific
binding sites for thrombin have been identified on hepatocytes, we
characterized the effect of thrombin on hepatocyte PAI- 1 production.
Incubation of Hep G2 cells with human alpha-thrombin resulted in a dose-
and time-dependent increase in the concentration of PAI-1 in conditioned
media. This effect was inhibited completely by hirudin and by antithrombin
III. Steady-state levels of both the 3.2-kb and 2.2-kb forms of PAI-1 mRNA
increased after stimulation of the cells with thrombin, indicating that
thrombin influences PAI-1 expression in Hep G2 cells at the
pretranslational level. Incubation of Hep G2 cells with alpha-thrombin and
either platelet lysates or purified transforming growth factor-beta
(TGF-beta), both previously shown to augment hepatocyte PAI-1 expression,
resulted in a synergistic increase in the concentration of PAI-1 in
conditioned media. PAI-1 mRNA appeared to be synergistically increased as
well. Thus, thrombin increases expression of both PAI-1 protein and mRNA in
Hep G2 cells and exerts synergistic effects with TGF-beta. These results
underscore the potential importance of inhibition of thrombin under
conditions in which thrombolysis is induced pharmacologically.
Volume 79,
Issue 1,
pp. 75-81,
01/01/1992
Copyright © 1992 by The American Society of Hematology
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