title: Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C.
abstract: Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but <10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.
authors: Blood Research Institute, Milwaukee, WI 53226, USA.
authors: Edward J
authors: EJ
authors: Kerschen
authors: José A
authors: JA
authors: Fernandez
authors: Brian C
authors: BC
authors: Cooley
authors: Xia V
authors: XV
authors: Yang
authors: Rashmi
authors: R
authors: Sood
authors: Laurent O
authors: LO
authors: Mosnier
authors: Francis J
authors: FJ
authors: Castellino
authors: Nigel
authors: N
authors: Mackman
authors: John H
authors: JH
authors: Griffin
authors: Hartmut
authors: H
authors: Weiler
mesh_terms: D000818:Animals; D017209:Apoptosis; D002463:Cell Membrane Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D015202:Protein Engineering; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D008070:Lipopolysaccharides; D011486:Protein C