title: Aurintricarboxylic acid upregulates the thrombomodulin expression of endothelial cells and peripheral blood monocytes.
abstract: Thrombomodulin has a central role in the regulation of coagulation through its ability to promote generation of the potent anticoagulant, activated protein C. Aurintricarboxylic acid (ATA) has been reported to inhibit platelet function by blocking von Willebrand factor binding to platelet glycoprotein Ib and to impede thrombosis development in vivo. In the present study, we demonstrated a novel antithrombotic effect of ATA. The surface thrombomodulin expression of endothelial cells and peripheral blood monocytes was upregulated by ATA in a dose-dependent and time-dependent manner. ATA also increased the mRNA level of endothelial thrombomodulin in a dose-dependent manner. Tumor necrosis factor (TNF)-alpha (50 ng/ml) or lipopolysaccharide (20 microg/ml) downregulated the expression of endothelial thrombomodulin. Blocking of nuclear factor-kappaB by parthenolide effectively inhibited the TNF-alpha-induced thrombomodulin downregulation of endothelial cells. ATA increased endothelial thrombomodulin expression that was downregulated by TNF-alpha or lipopolysaccharide, in a dose-dependent manner. The inhibition of small G proteins of the Rho family by the Clostridium difficile toxin B-1,0643 did not increase thrombomodulin expression of endothelial cells, and ATA did not activate Rac1 in endothelial cells. These findings provide, at least in part, a novel platelet-independent mechanism of ATA that may explain the demonstrated antithrombotic efficacy of ATA.
authors.affiliation: Department of Laboratory Medicine, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kim
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Kim
authors.forename: Kyou-Sup
authors.initials: KS
authors.lastname: Han
authors.forename: Han-Ik
authors.initials: HI
authors.lastname: Cho
mesh_terms: D000328:Adult; D001312:Aurintricarboxylic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018180:Thrombomodulin / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D015854:Up-Regulation / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors
chemical_list: D001427:Bacterial Toxins; C488583:Clostridium difficile lethal toxin B; D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; C107953:RAC1 protein, human; D012333:RNA, Messenger; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D001312:Aurintricarboxylic Acid; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein