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(Circulation Research. 2007;100:1174.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Protease Nexin-1 Interacts With Thrombomodulin and Modulates Its Anticoagulant Effect

Marie-Christine Bouton, Laurence Venisse, Benjamin Richard, Cécile Pouzet, Véronique Arocas, Martine Jandrot-Perrus

From the INSERM, U698, CHU Xavier Bichat (M.-C.B., L.V., B.R., V.A., M.J.-P.), Paris, France; IFR 02, Faculté Médecine Xavier Bichat (C.P.), Paris, France.

Correspondence to Dr Marie-Christine Bouton, Unité INSERM U698, CHU Xavier Bichat, 46 rue Henri Huchard 75877 Paris Cedex 18, France. E-mail mcbouton{at}bichat.inserm.fr

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.

Key Words: protease nexin-1 • thrombin • thrombomodulin • serpins • endothelial cells

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