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J. Biol. Chem., Vol. 279, Issue 11, 10346-10356, March 12, 2004

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Protease Nexin-1 Inhibits Plasminogen Activation-induced Apoptosis of Adherent Cells^*

Patrick Rossignol, Benoît Ho-Tin-Noé, Roger Vranckx, Marie-Christine Bouton, Olivier Meilhac, H. Roger Lijnen¶, Marie-Claude Guillin, Jean-Baptiste Michel, and Eduardo Anglés-Cano||

From the INSERM U460, Centre Hospitalier Universitaire Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Cedex, Paris 18, France, INSERM EMI348, Unité de Formation et de Recherche de Médecine X. Bichat, 16 rue Henri Huchard, 75870 Cedex, Paris 18, France, and the ^¶Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Degradation of adhesive glycoproteins by plasmin is implicated in cell migration. In this study, we further explored the role of plasminogen activation in cell adhesion and survival and show that uncontrolled plasminogen activation at the cell surface may induce cell detachment and apoptosis. We hypothesized that this process could be prevented in adherent cells by expression of protease nexin-1, a potent serpin able to inhibit thrombin, plasmin, and plasminogen activators. Using two- and three-dimensional culture systems, we demonstrate that Chinese hamster ovary fibroblasts constitutively express tissue-type plasminogen activator and efficiently activate exogenously added plasminogen in a specific and saturable manner (K_m = 46 nM). The formation of plasmin results in proteolysis of fibronectin and laminin, which is followed by cell detachment and apoptosis. Protease nexin-1 expressed by transfected cells significantly inhibited the activity of plasmin and tissue-type plasminogen activator via the formation of inhibitory complexes and prevented cell detachment and apoptosis. In conclusion, protease nexin-1 may be an important anti-apoptotic factor for adherent cells. This cell model could be a useful tool to evaluate therapeutic agents such as serpins in vascular pathologies involving pericellular protease-protease inhibitor imbalance.

Received for publication, October 6, 2003 , and in revised form, November 25, 2003.

^* This work was supported by INSERM and by grants from the Leducq Foundation and the Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 33-1-4025-8611; Fax: 33-1-4025-86-10; E-mail: angles{at}infobiogen.fr.

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