Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice.
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.
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Hai Po H
HP
Liang
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Edward J
EJ
Kerschen
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Sreemanti
S
Basu
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Irene
I
Hernandez
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Mark
M
Zogg
Department of Pediatrics, Medical College of Wisconsin, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI;
Shuang
S
Jia
Department of Pediatrics, Medical College of Wisconsin, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI;
Martin J
MJ
Hessner
Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA;
Raffaella
R
Toso
Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St Louis, MO;
Alireza R
AR
Rezaie
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA;
José A
JA
Fernández
Division of Hematology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA;
Rodney M
RM
Camire
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA; and Center for Thrombosis and Hemostasis, Mainz, Germany.
Wolfram
W
Ruf
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA;
John H
JH
Griffin
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;
Hartmut
H
Weiler
D000818:Animals; D005165:Factor V / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D017293:Protein S / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013211:Staphylococcus aureus; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
D011486:Protein C; D017293:Protein S; C095381:factor V Leiden; D005165:Factor V; D013925:Thromboplastin