'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage.
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.
Kaneider
Nicole C
NC
Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Leger
Andrew J
AJ
Agarwal
Anika
A
Nguyen
Nga
N
Perides
George
G
Derian
Claudia
C
Covic
Lidija
L
Kuliopulos
Athan
A
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
D044463:Receptor, PAR-1; D044464:Receptor, PAR-2