Faculty Collaboration Database

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. Blood 2015 Nov 19;126(21):2415-23

Date

09/06/2015

Pubmed ID

26341257

Pubmed Central ID

PMC4653768

DOI

10.1182/blood-2015-05-644401

Scopus ID

2-s2.0-84948989408 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

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 H

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Shuang Jia Biostatistician III in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Factor V
Mice
Mice, Transgenic
Protein C
Protein S
Sepsis
Signal Transduction
Staphylococcal Infections
Staphylococcus aureus
Thromboplastin