Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. Blood 2015 Nov 19;126(21):2415-23
Date
09/06/2015Pubmed ID
26341257Pubmed Central ID
PMC4653768DOI
10.1182/blood-2015-05-644401Scopus ID
2-s2.0-84948989408 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
The key effector molecule of the natural protein C pathway, activated protein C (aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. Coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. In this study, using a mouse model of Staphylococcus aureus sepsis, we demonstrate marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC. aPC resistance of factor (f)V due to the R506Q Leiden mutation protected against detrimental anticoagulant effects of aPC therapy but also abrogated the anti-inflammatory and mortality-reducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. We found that procofactor V (cleaved by aPC at R506) and protein S were necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The anti-inflammatory cofactor function of fV involved the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities did not involve proteolysis of activated coagulation factors Va and VIIIa. These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection.
Author List
Liang HP, Kerschen EJ, Basu S, Hernandez I, Zogg M, Jia S, Hessner MJ, Toso R, Rezaie AR, Fernández JA, Camire RM, Ruf W, Griffin JH, Weiler HAuthors
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of WisconsinHartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsFactor V
Mice
Mice, Transgenic
Protein C
Protein S
Sepsis
Signal Transduction
Staphylococcal Infections
Staphylococcus aureus
Thromboplastin