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J. Biol. Chem., Vol. 280, Issue 20, 19808-19814, May 20, 2005
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Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling*
From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor (EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1-/- mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up- and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even up-regulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.
Received for publication, January 20, 2005 , and in revised form, March 11, 2005.
* This research was supported by National Institutes of Health Grants HL 78614 and HL 48752 (to W. R.), HL 73318 (to M. R.), and by a Junior Faculty Scholar Award from the American Society of Hematology (to M. R.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental data.
To whom correspondence should be addressed: The Scripps Research Institute, Dept. of Immunology VB-4, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8226; Fax: 858-784-7276; E-mail: riewald{at}scripps.edu.
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