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Arteriosclerosis, Thrombosis, and Vascular Biology. 1993;13:1119-1123

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Arteriosclerosis and Thrombosis, Vol 13, 1119-1123, Copyright © 1993 by American Heart Association

ARTICLES

Recombinant human thrombomodulin attenuates human endothelial cell activation by human thrombin

JF Parkinson, NU Bang and JG Garcia
Eli Lilly and Co, Indianapolis, Ind.

Two glycoforms of recombinant human thrombomodulin (TM; TMD1-105 and TMD1-75), an endothelial cell membrane protein, were tested for their ability to alter thrombin-induced activation of cultured human umbilical vein endothelial cells (HUVECs). After stimulation with 10 nmol/L thrombin, HUVEC generation of inositol-1,4,5-trisphosphate (IP3), a potent Ca(2+)-mobilizing second messenger, was dose- dependently blocked by TMD1-105. Both TMD1-105 (IC50 = 10 nmol/L) and TMD1-75 (IC50 = 100 nmol/L) blocked the enhanced prostacyclin synthesis by HUVEC monolayers treated with 10 nmol/L thrombin. HUVEC monolayer permeability to Evans blue dye-labeled albumin increased from 0.125 +/- 0.06 microL/min in control experiments to 0.380 +/- 0.09 microL/min after treatment with 100 nmol/L thrombin (P < .05). Incubation of HUVECs with TMD1-105 alone (600 nmol/L) had no effect (0.114 +/- 0.04 microL/min) on basal permeability. In contrast, incubation of 100 nmol/L thrombin with 600 nmol/L TMD1-105 reduced this increase in HUVEC permeability to almost control levels (0.142 +/- 0.06 microL/min). These results demonstrate that recombinant human TM, a potent in vitro anticoagulant, also functions as an antagonist of thrombin receptor- mediated HUVEC activation. In addition to its anticoagulant functions, the high-affinity endothelial cell receptor TM may play a role in modulating endothelial cell activation by thrombin.


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