doi: 10.1161/ATVBAHA.109.195701
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© 2009 American Heart Association, Inc.
Editorials |
Dimorphisms in the Membrane-Spanning Domain of EPCR Impact Systemic Coagulation
From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation; the Howard Hughes Medical Institute; and the Departments of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City.
Correspondence to Charles T. Esmon, Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail esmonc@omrf.ouhsc.edu
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
The role of vascular coagulation receptors, particularly modest changes in the levels of these proteins in terms of controlling downstream coagulation factor activation, remains largely unknown. The study reported by Ireland and colleagues in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology1 demonstrates that a moderately common dimorphism in the endothelial cell protein C receptor (EPCR) influences the levels of markers of ongoing coagulation (Figure). Several of the key components, thrombomodulin and the EPCR, are subject to downregulation by inflammatory mediators that could play a role potentially in local thrombotic events. EPCR is an important regulatory factor in that it binds protein C and activated protein C,2 augments protein C activation by the thrombin-thrombomodulin complex,3 facilitates activated protein C cytoprotective activity,4 binds factor VII and VIIa,5–6 and leads to the internalization and degradation of both factor VII and protein C.7 In addition, the EPCR gene has a relatively common dimorphism in which there is a Ser to Gly substitution in the membrane spanning domain. This substitution leads to increased shedding, probably catalyzed by TACE (tumor necrosis factor 
- converting enzyme),8 of EPCR as a soluble form from the endothelial cell surface.9 Shedding increases the levels of circulating EPCR at the expense of membrane-bound EPCR and hence should impact EPCR function. Indeed the 3 genotypes Ser-Ser, Ser-Gly, and Gly-Gly were identified in the human population and studied in the analysis by Ireland et al1 for alterations in a variety of markers of ongoing coagulation, particularly factor VII and VIIa
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