Journal
BLOOD
Volume 119, Issue 12, Pages 2914-2921Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-05-353409
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Funding
- Union Temporal de Empresas project Centre for Applied Medical Research
- Instituto de Salud Carlos III [PI08/1349, PI10/01432, RECAVARD06/0014/0008]
- Health Department, Gobierno de Navarra [15/09]
- Education Department, Gobierno de Navarra
- Sociedad Espanola de Trombosis y Hemostasia
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The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A(2) (sPLA(2)-V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (lysoPCh) and platelet activating factor (PAF). Remarkably, lysoPCh and PAF impaired the protein C binding ability of sEPCR. Inhibition of sPLA(2)-V, responsible for lysoPCh and PAF generation, improved APC binding to endothelial cells. EPCR-dependent protein C activation and APC antiapoptotic effect were thus significantly enhanced. In contrast, endothelial cell supplementation with sPLA(2)-V inhibited both APC generation and its antiapoptotic effects. We conclude that APC generation and function can be modulated by changes in phospholipid occupancy of its endothelial cell receptor. (Blood. 2012;119(12):2914-2921)
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