Secretory group V phospholipase A2 : a new player in thrombosis?

Abstract

The protein C anticoagulant system plays a critical role in the regulation of hemostasis and inflammation. Binding of protein C to endothelial cell protein C receptor (EPCR) and the subsequent activation of EPCR-bound protein C by thrombin–thrombomodulin are the key steps in the protein C anticoagulant system. Activated protein C (APC)-mediated cell signaling, supported by its binding to EPCR or independently of EPCR, activates anti-inflammatory and cytoprotective pathways [1]. Therefore, pathophysiologic conditions that impair the interaction of protein C with EPCR have the potential to decrease APC generation. Such reduced binding of protein C to EPCR may not only contribute to thrombotic disorders, but also result in the loss of endogenous APCmediated cytoprotection. EPCR shares a sequence and a three-dimensional homology with the major histocompatibility class 1/CD1 family of proteins, particularly CD1d [2,3]. Similarly to the CD1 family proteins, EPCR has a tightly bound phospholipid in the antigen-presenting groove [3]. This similarity led to an initial belief that EPCR may play a role in presenting protein C/APC or lipid antigen in inflammatory cells [2]. However, at present, there is no evidence that EPCR plays a role in presenting lipid antigens to inflammatory cells. However, the presence of the lipid in EPCR seems to be essential for EPCR binding to protein C, as extraction of the lipid from EPCR abolishes protein C binding [3]. Molecular dynamic simulations of phosphatidylethanolamine-bound and phosphatidylethanolamine-unbound forms of EPCR reveal that the lipid probably maintains the conformation of EPCR that is necessary for the interaction with its ligands [4]. Recently, Hermida et al. showed that phosphatidylcholine (PC) is the major phospholipid bound to human EPCR, and that lipid exchange can occur in EPCR, just as it can in CD1d [5]. They also showed that the exchange of PC in EPCR for lyso-PC or platelet-activating factor (PAF) impaired the ability of EPCR to bind protein C and factor VII, indicating that EPCR function could be modulated by a change in the identity of the phospholipid in the hydrophobic groove of EPCR. Secretory group V phospholipase A2 (sPLA2-V), an enzyme that can be upregulated in a variety of inflammatory conditions and that metabolizes PC to lyso-PC, is capable of modulating both the binding of protein C to EPCR and the generation of APC on endothelial cells [5]. These data have raised the possibility that sPLA2-V may exert prothrombotic and proinflammatory effects through modification of the bound lipid in EPCR (Fig. 1). In a study published in this issue of the Journal of Thrombosis and Haemostasis, Tamayo et al. provide evidence that sPLA2-V does indeed play a thrombogenic role in vivo [6]. The data presented in the article show that overexpression of sPLA2-V in mice by hydrodynamic gene delivery impairs the ability of mice to activate protein C. More importantly, sPLA2-V overexpression accelerates thrombus formation in a carotid artery laser thrombosis model. When EPCR was blocked with a blocking antibody, sPLA2-V overexpression no longer had a significant influence on APC generation or thrombus formation. Furthermore, administration of manoalide, an inhibitor of sPLA2-V, significantly increased APC generation and moderately reduced thrombus formation in wild-type mice. From these data, the authors conclude that sPLA2-V downregulates protein C activation in vivo by encrypting EPCR, and thus promotes thrombus formation. The authors raise the possibility of targeting sPLA2-V activity as an antithrombotic strategy. Correspondence: L. Vijaya Mohan Rao, Department of Cellular and Molecular Biology, Center for Biomedical Research, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA. Tel.: +1 903 877 7332; fax: +1 903 877 7426. E-mail: Vijay.Rao@uthct.edu

DOI: 10.1111/jth.12729

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Cite this paper

@article{Rao2014SecretoryGV, title={Secretory group V phospholipase A2 : a new player in thrombosis?}, author={L Vijaya Mohan Rao}, journal={Journal of thrombosis and haemostasis : JTH}, year={2014}, volume={12 11}, pages={1918-20} }