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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1515-1522. Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-05-1896. This Article Full Text (PDF) All Versions of this Article: 2004-05-1896v1 105/4/1515    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Perez-Casal, M. Articles by Toh, C. H Search for Related Content PubMed PubMed Citation Articles by Perez-Casal, M. Articles by Toh, C. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 18, 2004 Accepted October 4, 2004 Activated protein C induces the release of microparticle-associated endothelial protein C receptor Margarita Perez-Casal, Colin Downey, Kenji Fukudome, Gernot Marx, and Cheng H Toh* Roald Dahl Haemostasis & Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, United Kingdom Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan Department of Anaesthesia & Intensive Care Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom * Corresponding author; email: toh{at}liv.ac.uk. Activated protein C (APC) treatment is now used for patients with severe sepsis. We investigated its effect in vitro on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release that is not inhibited by metalloproteinase inhibitors. Exposure of human umbilical vein endothelial cells or monocytes to APC (6.25 to 100nM) results in the release of EPCR-containing microparticles, as demonstrated by confocal microscopy and characterised through flow cytometry, ELISA quantitation of isolated microparticles and Western blotting. The phenomenon is time and concentration dependent and requires the APC active site, EPCR and protease activated receptor 1 (PAR1) on endothelial cells. Neither protein C, boiled or D-Phe-Pro-Arg-chloromethylketone-blocked APC can induce microparticle formation and antibody-blockade of EPCR or PAR1 cleavage and activation abrogated this APC action. Co-incubation with hirudin does not alter the APC effect. The released microparticle-bound is full-length EPCR (49kDa) and APC retains factor V inactivating activity. Whilst tumor necrosis factor-(10ng/ml) can also induce microparticle-associated EPCR release to a similar extent as APC (100nM), it is only APC-induced microparticles that contain bound APC. This novel observation could provide new insights into the consequences of APC therapy in the septic patient. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C Pericleous, I Giles, and A Rahman Are endothelial microparticles potential markers of vascular dysfunction in the antiphospholipid syndrome? Lupus, July 1, 2009; 18(8): 671 - 675. [Abstract] [PDF] O. Morel, F. Toti, N. Morel, and J.-M. Freyssinet Microparticles in endothelial cell and vascular homeostasis: are they really noxious? Haematologica, March 1, 2009; 94(3): 313 - 317. [Full Text] [PDF] M. Perez-Casal, C. Downey, B. Cutillas-Moreno, M. Zuzel, K. Fukudome, and C. H. 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Tucker, O. J. T. McCarty, J. H. Griffin, and S. R. Hanson Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates Blood, April 1, 2007; 109(9): 3733 - 3740. [Abstract] [Full Text] [PDF] O. Morel, F. Toti, B. Hugel, B. Bakouboula, L. Camoin-Jau, F. Dignat-George, and J.-M. Freyssinet Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2594 - 2604. [Abstract] [Full Text] [PDF] M. Riewald and W. Ruf Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling J. Biol. Chem., May 20, 2005; 280(20): 19808 - 19814. [Abstract] [Full Text] [PDF]

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