Submitted June 28, 2006
Accepted September 14, 2006
Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice
Xunzhen Zheng, Weihong Li, Jian-Ming Gu, Dongfeng Qu, Gary L. Ferrell, Naomi L. Esmon, and Charles T. Esmon*
Oklahoma Medical Research Foundation, the Howard Hughes Medical Institute, United States
Berlex Biosciences, United States
University of Oklahoma Health Sciences Center, United States
* Corresponding author; email: esmonc{at}omrf.ouhsc.edu.
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 approximately 30%. Infusion of factor Xa with phopholipid 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 to wild type mice. We also generated mice in which one allele of full length EPCR was replaced by sEPCR (Procr s/+). Compared to Procr +/- mice, Procr s/+ mice had 5 fold higher sEPCR and similar mEPCR levels. Procr +/- and Procr s/+ mice generated similar levels of APC upon thrombin infusion. They also exhibited a similar coagulant response upon factor Xa/phospholipid infusion. Only supra-physiological 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.
