title: Group V secretory phospholipase A2 impairs endothelial protein C receptor-dependent protein C activation and accelerates thrombosis in vivo.
abstract: BACKGROUND
  Endothelial protein C receptor (EPCR) must be bound to a molecule of phosphatidylcholine (PC) to be fully functional, i.e. to interact with protein C/activated protein C (APC) properly. PC can be replaced with other lipids, such as lysophosphatidylcholine or platelet-activating factor, by the action of group V secretory phospholipase A2 (sPLA2-V), an enzyme that is upregulated in a variety of inflammatory conditions. Studies in purified systems have demonstrated that the substitution of PC notably impairs EPCR function in a process called EPCR encryption.
  
  
  OBJECTIVE
  To analyze whether sPLA2-V was able to regulate EPCR-dependent protein C activation in vivo, and its impact on thrombosis and the hemostatic system.
  
  
  METHODS
  Mice were transfected with sPLA2-V by hydrodynamic gene delivery. The effects on thrombosis were studied with the laser carotid artery occlusion model, and APC generation capacity was measured with ELISA. Global hemostasis was analyzed with thromboelastometry.
  
  
  RESULTS
  We found that sPLA2-V overexpression in mice significantly decreased their ability to generate APC. Furthermore, a murine carotid artery laser thrombosis model revealed that higher sPLA2-V levels were directly associated with faster artery thrombosis.
  
  
  CONCLUSIONS
  sPLA2-V plays a thrombogenic role by impairing the ability of EPCR to promote protein C activation.
authors: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: I
authors: I
authors: Tamayo
authors: S E
authors: SE
authors: Velasco
authors: C
authors: C
authors: Puy
authors: C T
authors: CT
authors: Esmon
authors: M G
authors: MG
authors: Dichiara
authors: R
authors: R
authors: Montes
authors: J
authors: J
authors: Hermida
mesh_terms: D000818:Animals; D016893:Carotid Stenosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D054505:Group V Phospholipases A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006487:Hemostasis; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008813:Mice, Inbred ICR; D011486:Protein C / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D013997:Time Factors
chemical_list: D000074283:Endothelial Protein C Receptor; D004791:Enzyme Inhibitors; C080248:Procr protein, mouse; D011486:Protein C; D011956:Receptors, Cell Surface; D054505:Group V Phospholipases A2; C516299:PLA2G5 protein, human
keywords: activated protein C resistance; endothelial cell protein C receptor; group V secretory phospholipase A2; protein C; thrombosis