Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice.
Recent studies have shown that endothelial protein C receptor (EPCR) polymorphisms and soluble EPCR levels are associated with thrombotic diseases. It is unknown whether membrane EPCR (mEPCR) heterozygosity and/or physiologically elevated sEPCR levels directly impact the hemostatic balance and the outcome of endotoxemia. In these studies, thrombin infusion experiments revealed that EPCR heterozygosity (Procr+/-) impaired protein C activation by approximately 30%. Infusion of factor Xa with phospholipid demonstrated that the Procr+/- genotype increased the coagulant response relative to wild-type mice. Challenge of the Procr+/- mice with lipopolysaccharide (LPS) did not significantly exaggerate their response compared with wild-type mice. We also generated mice in which one allele of full-length EPCR was replaced by sEPCR (Procrs/+). Compared with Procr+/- mice, Procrs/+ mice had 5-fold higher sEPCR and similar mEPCR levels. Procr+/- and Procrs/+ mice generated similar levels of activated protein C (APC) upon thrombin infusion. They also exhibited a similar coagulant response upon factor Xa/phospholipid infusion. Only supraphysiologic levels of sEPCR could influence protein C activation and exaggerate the coagulant response. In conclusion, mEPCR, but not physiologically elevated sEPCR, regulated protein C activation. Procr heterozygosity results in a mild increase of thrombosis tendency and little influence on the response to endotoxin.
Zheng
Xunzhen
X
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, the Howard Hughes Medical Institute, Oklahoma City 73104, USA.
Li
Weihong
W
Gu
Jian-Ming
JM
Qu
Dongfeng
D
Ferrell
Gary L
GL
Esmon
Naomi L
NL
Esmon
Charles T
CT
D000818:Animals; D000074283:Endothelial Protein C Receptor; D019446:Endotoxemia / Q000209:etiology*; D006023:Glycoproteins / Q000502:physiology*; D006487:Hemostasis; D006579:Heterozygote; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D011486:Protein C / Q000378:metabolism; D011956:Receptors, Cell Surface; D012995:Solubility; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology
D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C080248:Procr protein, mouse; D011486:Protein C; D011956:Receptors, Cell Surface; D013917:Thrombin