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J. Biol. Chem., Vol. 283, Issue 40, 27220-27229, October 3, 2008

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Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis^*

Jean-François Cailhier¹, Isabelle Sirois², Patrick Laplante, Stéphanie Lepage, Marc-André Raymond, Nathalie Brassard, Alexandre Prat, Renato V. Iozzo^¶, Alexey V. Pshezhetsky^||, and Marie-Josée Hébert³

From the Research Centre, Centre Hospitalier Universitaireé de Montréal (CHUM) and Montreal Cancer Institute and Neuroimmunology Research Laboratory, Research Centre, CHUM, Université de Montréal, Montreal, Quebec H2L 4M1, Canada, ^¶Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ^||Department of Medical Genetics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec H3T 1C5, Canada

Proteolysis of extracellular matrix components and the production of cryptic bioactive factors play key roles in vascular remodeling. We showed previously that extracellular matrix proteolysis is triggered by the apoptosis of endothelial cells (EC), resulting in the release of an anti-apoptotic C-terminal fragment of endorepellin (LG3). Here, we characterize the endorepellin-cleaving proteases released by apoptotic EC using a multifaceted proteomics strategy. Cathepsin L (CathL), a cysteine protease known to be associated with cardiovascular disease progression in animal models and humans, was isolated from medium conditioned by apoptotic EC. CathL cleaved recombinant endorepellin in vitro, leading to LG3 release. Inhibition of CathL activity in EC exposed to pro-apoptotic stimuli prevented LG3 release without modulating the development of apoptosis in EC. Inhibition of caspase-3 activation in EC with the biochemical inhibitor DEVD-fluoromethyl ketone or small interfering RNAs concomitantly prevented CathL release by EC, LG3 production, and the development of paracrine anti-apoptotic activity. These data demonstrate that caspase-3 activation is a novel pathway of importance for triggering extracellular CathL release and the cleavage of extracellular matrix components.

Received for publication, February 12, 2008 , and in revised form, July 23, 2008.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP-15447 (to M.-J. H.) and MOP-66980 (to A. V. P.) and a grant from the Fonds de la Recherche en Santé du Québec (Interdisciplinary group grant on predictors of rejection (to M.-J. H.)). 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.

¹ Recipient of a Bristol-Myers Squibb Canada Cardiovascular Research Fellowship.

² Recipient of a training fellowship from the Canadian Institutes of Health Research.

³ Holds the Shire Chair in Nephrology, Transplantation, and Renal Regeneration of the University of Montreal. To whom correspondence should be addressed: CRCHUM, 1560 Sherbrooke St. East, Montreal QC H2L 4M1, Canada. Tel.: 514-890-8000 (ext. 25393); Fax: 514-412-7624; E-mail: marie-josee.hebert.chum{at}ssss.gouv.qc.ca.

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