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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1.)
© 2008 American Heart Association, Inc.

Editorials

Protective Signaling Pathways of Activated Protein C in Endothelial Cells

Matthias Riewald; Reto A. Schuepbach

From the Department of Immunology, The Scripps Research Institute, La Jolla, CA.

Correspondence to Matthias Riewald, MD, Department of Immunology SP30-3040, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail riewald@scripps.edu.

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Activated protein C (APC) has been reported to improve survival in patients with severe sepsis.¹ Protein C (PC) is physiologically activated on the endothelial cell surface by the key procoagulant enzyme thrombin, and APC downregulates thrombin formation in a negative feedback loop.² This anticoagulant effect of APC is unlikely to explain its benefit in systemic inflammation because other anticoagulants did not improve survival in septic patients. How the protective effects of APC in systemic inflammation are mediated has thus received a considerable amount of attention in recent years.

See ATVB 2007;2634–2641.

In vitro studies have shown that incubation of cultured endothelial cells with APC leads to a number of potentially antiinflammatory cellular changes. These include downregulation of the expression of adhesion molecules, enhanced barrier function in cell monolayers, and effects on gene expression that result in decreased susceptibility to apoptosis. Most of these cellular responses have been shown to require the binding of APC to endothelial cell protein C receptor (EPCR) and cleavage-mediated activation of protease activated receptor-1 (PAR1).^3–6 EPCR may not only enhance activation of PAR1 by APC but also modify downstream responses through other mechanisms.^7–9 EPCR is a transmembrane receptor with a very short cytoplasmic domain and an extracellular domain that binds both PC and APC. EPCR recruits and positions PC/APC on the cell surface, and EPCR binding enhances activation of PC. PAR1 is the prototypical thrombin receptor and belongs to a family of 7-transmembrane G protein–coupled receptors. Enzymatic cleavage of PAR1 exposes a new extracellular N terminus . . . [Full Text of this Article]

Related Article:

Activated Protein C Decreases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand by an EPCR- Independent Mechanism Involving Egr-1/Erk-1/2 Activation

Lee A. O’Brien, Mark A. Richardson, Sean F. Mehrbod, David T. Berg, Bruce Gerlitz, Akanksha Gupta, and Brian W. Grinnell
Arterioscler Thromb Vasc Biol 2007 27: 2634-2641. [Abstract] [Full Text] [PDF]

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