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An atherogenic stimulus homocysteine inhibits cofactor activity of
thrombomodulin and enhances thrombomodulin expression in human umbilical
vein endothelial cells
T Hayashi, G Honda and K Suzuki
Department of Molecular Biology on Genetic Disease, Mie University School
of Medicine, Tsu City, Japan.
Thrombomodulin plays a role as a cofactor for thrombin-catalyzed activation
of protein C on endothelial cells. We examined the effect of homocysteine,
a stimulant of atherosclerosis and thrombotic disease, on the cofactor
activity and protein level of thrombomodulin and also on the expression of
thrombomodulin in endothelial cells. Homocysteine inhibited the cofactor
activity of thrombomodulin both on the surface of endothelial cells and in
the whole cells dose- and time-dependently, and maximal inhibition of the
cofactor activity occurred after a 3- to 6-hour incubation with 10 mmol/L
homocysteine (10% of initial activity). Homocysteine also decreased the
amount of intact (unreduced) thrombomodulin in endothelial cells. However,
at the same condition the total protein level (reduced and unreduced form)
of thrombomodulin, determined by dot immunoblot analysis using the
monoclonal antibody that recognized both reduced and unreduced
thrombomodulin, decreased slightly, and the mRNA level of thrombomodulin
showed a twofold to three-fold increase. After 24 hours of incubation, the
cofactor activity and total protein level of thrombomodulin were 60% and
165% of the initial values, respectively. When purified thrombomodulin
fixed to a microwell plate was treated with homocysteine, both cofactor
activity and thrombin-binding ability to the thrombomodulin were decreased
in proportion to the concentration of homocysteine. These findings suggest
that homocysteine directly inhibited the cofactor activity of
thrombomodulin on endothelial cells by reducing the disulfide-bond rich
epidermal growth factor-like structures of thrombomodulin. This would a
result in the decrease of the antithrombotic property of endothelium and
may also trigger off the synthesis of mRNA and protein of thrombomodulin to
maintain the antithrombotic properties of the cells.
Volume 79,
Issue 11,
pp. 2930-2936,
06/01/1992
Copyright © 1992 by The American Society of Hematology
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