Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine

S R Lentz; J E Sadler

doi:10.1172/JCI115514

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Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine

Journal article

Open access

Peer reviewed

Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine

S R Lentz and J E Sadler

The Journal of clinical investigation, Vol.88(6), pp.1906-1914

12/1991

DOI: 10.1172/JCI115514

PMCID: PMC295763

PMID: 1661291

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https://doi.org/10.1172/JCI115514View

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Abstract

Elevated levels of plasma homocysteine are associated with both venous and arterial thrombosis. Homocysteine inhibits the function of thrombomodulin, an anticoagulant glycoprotein on the endothelial surface that serves as a cofactor for the activation of protein C by thrombin. The effects of homocysteine on thrombomodulin expression and protein C activation were investigated in cultured human umbilical vein endothelial cells and CV-1(18A) cells that express recombinant human thrombomodulin. Addition of 5 mM homocysteine to endothelial cells produced slight increases in thrombomodulin mRNA and thrombomodulin synthesis without affecting cell viability. In both cell types, thrombomodulin synthesized in the presence of homocysteine remained sensitive to digestion with endoglycosidase H and failed to appear on the cell surface, suggesting impaired transit along the secretory pathway. In a cell-free protein C activation assay, homocysteine irreversibly inactivated both thrombomodulin and protein C in a process that required free thiol groups and was inhibited by the oxidizing agents diamide or N-ethylmaleimide. By inhibiting both thrombomodulin surface expression and protein C activation, homocysteine may contribute to the development of thrombosis in patients with cystathionine beta-synthase deficiency.

Receptors, Thrombin

Oxidation-Reduction

Thrombosis - etiology

Homocysteine - pharmacology

Humans

Cells, Cultured

Platelet Membrane Glycoproteins - biosynthesis

Ethylmaleimide - pharmacology

Chondroitin Sulfates - pharmacology

Glycosylation

Receptors, Cell Surface - biosynthesis

Protein C - metabolism

Details

Title: Subtitle: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine
Creators: S R Lentz - Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
J E Sadler
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.88(6), pp.1906-1914
DOI: 10.1172/JCI115514
PMID: 1661291
PMCID: PMC295763
ISSN: 0021-9738
eISSN: 1558-8238
Grant note: T32 HLBI 07088 / NHLBI NIH HHS HLBI 14147 / NHLBI NIH HHS
Language: English
Date published: 12/1991
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094215202771

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