Protease Nexin-1 Interacts with Thrombomodulin and Modulates Its Anticoagulant Effect.
From: Unité INSERM U698, CHU Xavier Bichat, Paris, France. mcbouton@bichat.inserm.fr
Circulation research
- Publish Date: Apr 2007
- ISSN: 1524-4571
- Volume: 100
- Issue: 8
- Pages: 1174-81
- Medium: Internet
- Language: English
- Citation (JAMA): Bouton Marie-Christine, Venisse Laurence, Richard Benjamin, et al. Protease Nexin-1 Interacts with Thrombomodulin and Modulates Its Anticoagulant Effect.. Circ. Res. Apr 2007;100:1174-81
Abstract
The endothelial cell membrane glycoprotein thrombomodulin (TM) plays a critical role in the regulation of coagulation. TM is an essential cofactor in protein C activation by thrombin, and a direct inhibitor of thrombin-induced platelet activation and fibrinogen clotting. Protease nexin-1 (PN-1) is a serpin synthesized and secreted by a variety of cells including endothelial cells. PN-1 bound to the cell surface through interactions with glycosaminoglycans, is an efficient inhibitor of thrombin and controls thrombin-induced cell responses. An investigation of the interaction of PN-1 with TM using purified proteins and cultured human aortic endothelial cells was performed. Purified PN-1 was observed to bind to purified TM in a concentration-dependent manner. Double immunofluorescence studies indicated that PN-1 and TM were colocalized at the endothelial cell surface from which they were coprecipitated. Pretreatment of the cells with chondroitinase ABC greatly decreased the amount of the PN-1 associated to TM at the cell surface demonstrating the involvement of the TM chondroitin-sulfate chain in the formation of complexes. The inhibitory activity of the PN-1/TM complexes on the catalytic activity of thrombin, and on thrombin-induced fibrinogen clotting, was markedly enhanced when compared with the inhibitory activity of each partner. PN-1-overexpressing human aortic endothelial cells and PN-1-underexpressing human aortic endothelial cells exhibited respectively a significantly reduced ability and enhanced capacity to activate protein C. Furthermore, PN-1 decreased the cofactor activity of TM on thrombin activable fibrinolysis inhibitor activation by thrombin. These data show for the first time that PN-1 forms complexes with TM and modulates its anticoagulant activity.
Mesh Headings (Keywords): Amyloid beta-Protein Precursor, Blood Coagulation, Cells, Cultured, Endothelial Cells, Humans, Protein Binding, Receptors, Cell Surface, Thrombomodulin
Check for Full Text / PubMed Unique Identifier (PMID): 17379830
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