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'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage

Nature Immunology volume 8, pages 1303–1312 (2007)Cite this article

Abstract

Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.

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Figure 1: Effects of PAR1 agonist and antagonist pepducins on the survival of septic mice.
Figure 2: Effect of activation or inhibition of PAR1 on lung vascular permeability in septic mice.
Figure 3: Treatment of septic mice with PAR1-based pepducins inhibits DIC.
Figure 4: The beneficial effects of PAR1 agonists on endothelial barrier function require PAR2.
Figure 5: The protective effects of the PAR1-agonist pepducin on the survival, DIC and vascular permeability of septic mice require PAR2.
Figure 6: The endothelial barrier–restoring activity of thrombin and APC requires PAR1 and PAR2.
Figure 7: PAR1-PAR2 switching of Rac and Rho signaling in endotoxin-stimulated endothelium.

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Acknowledgements

We thank C. Edgell and J. Sondek (University of North Carolina, Chapel Hill) for EA.hy926 cells, GST-rhotekin and the GST-PAK pGEX4T constructs, and R. Buchsbaum (Tufts–New England Medical Center) for the Myc-tagged Rac constructs. Confocal FRET microscopy was done in the Tufts University Neuroscience Imaging Core Facility. Supported by the Austrian Science Fund (J-2342-B05 to N.C.K.), the American Heart Association (A.J.L.) and the National Institutes of Health (HL64701, HL57905 and CA122992 to A.K.; CA104406 to L.C.).

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Authors and Affiliations

  1. Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, 02111, Massachusetts, USA

    Nicole C Kaneider, Andrew J Leger, Anika Agarwal, Nga Nguyen, Lidija Covic & Athan Kuliopulos

  2. Department of Surgery, Tufts–New England Medical Center, Boston, 02111, Massachusetts, USA

    George Perides

  3. Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, 19477, Pennsylvania, USA

    Claudia Derian

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Contributions

N.C.K. and A.K. conceptualized and designed the experiments; N.C.K., A.J.L., A.A., N.N. and L.C. did the experiments; G.P. and C.D. generated and provided Par1−/− and Par2−/− mice and intellectual contributions; and N.C.K., L.C. and A.K. analyzed the data and prepared the manuscript.

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Correspondence to Athan Kuliopulos.

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C.D. is an employee of Johnson & Johnson Pharmaceutical Company.

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Kaneider, N., Leger, A., Agarwal, A. et al. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol 8, 1303–1312 (2007). https://doi.org/10.1038/ni1525

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