title: 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage.
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.
authors.affiliation: Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kaneider
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Leger
authors.forename: Anika
authors.initials: A
authors.lastname: Agarwal
authors.forename: Nga
authors.initials: N
authors.lastname: Nguyen
authors.forename: George
authors.initials: G
authors.lastname: Perides
authors.forename: Claudia
authors.initials: C
authors.lastname: Derian
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002450:Cell Communication; D002460:Cell Line; D042783:Endothelial Cells / Q000502:physiology*; D051379:Mice; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D014652:Vascular Diseases / Q000209:etiology
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2