Metalloproteolytic Release of Endothelial Cell Protein C Receptor

Xu, Jun; Qu, Dongfeng; Esmon, Naomi L.; Esmon, Charles T.

doi:10.1074/jbc.275.8.6038

Cited by 178 publications

(155 citation statements)

References 34 publications

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“…Thus, the decrease of TM observed in the present study may be attributed to TM shedding and release in damaged HUVECs due to LPS. In addition, sEPCR can be generated in vitro through proteolytic cleavage by metalloproteases, and this process is inducible by several inflammatory mediators (10). Therefore, UFH is able to protect TM and EPCR expression in endothelial cells during early endotoxemia, while anti-inflammatory agents and inhibitors of metalloproteases are also recommended for optimal protection of these protein C pathway components.…”

Section: Discussionmentioning

confidence: 99%

“…The endothelial cell layer provides an anticoagulant surface by expressing thrombomodulin (TM) and endothelial protein C receptor (EPCR), which support thrombin in generating APC (6,7). However, the protein C system is impaired during sepsis; APC is rapidly consumed during coagulation, while TM and EPCR are cleaved from the endothelial surface by proteases, including neutrophil elastase (8) and metalloproteases (9,10). Thus, a rapid drop in circulating APC, and concurrent rises in the serum levels of soluble TM (sTM) and soluble EPCR (sEPCR), are commonly observed in sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

et al. 2017

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Abstract. Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR in vitro using human umbilical vein endothelial cells (HUVECs). The in vivo data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS-induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose-dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS-induced activation of mitogen-activated protein kinase 14, proto-oncogene tyrosine-protein kinase Src and nuclear factor κB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

et al. 2017

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“…For example, a variety of G protein-coupled receptor signaling molecules and tyrosine kinases are known to be compartmentalized within the cholesterol/glycosphingolipid-rich cell membrane lipid rafts and caveolae (17,18). In fact, there is some evidence for EPCR being targeted to such membrane microdomains as demonstrated by a higher rate of proteolytic shedding of soluble EPCR (sEPCR) in the caveolin-overexpressing cells (19). Whether EPCR, PAR-1, and TM are colocalized in the membrane microdomains of endothelial cells is not known.…”

mentioning

confidence: 99%

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Bae

Yang

Rezaie

2007

Proc. Natl. Acad. Sci. U.S.A.

172

212

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Ever-increasing evidence in the literature suggests that the antiinflammatory and cytoprotective properties of activated protein C (APC) are mediated through its endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on endothelial cells. However, recent results monitoring the cleavage rate of PAR-1 on human umbilical vein endothelial cells, transfected with an alkaline phosphatase-PAR-1 fusion reporter construct, have indicated that the catalytic activity of thrombin toward PAR-1 is several orders of magnitude higher than that of APC. Because thrombin is required for generation of APC, and because it also functions in the proinflammatory pathways through the activation of PAR-1, it has been difficult to understand how APC can elicit protective cellular responses through the activation of PAR-1 when thrombin is present. In this study we provide a plausible answer to this question by demonstrating that the critical receptors required for both protein C activation (thrombomodulin and EPCR) and APC cellular signaling (EPCR and PAR-1) pathways are colocalized in the membrane lipid rafts in endothelial cells. We further show that the APC cleavage of PAR-1 on cells transfected with a PAR-1 cleavage reporter construct is not sensitive to the cofactor function of EPCR. Thus, the colocalization of EPCR and PAR-1 in lipid rafts is a key requirement for the cellular signaling activity of APC. Thrombomodulin colocalization with these receptors on the same membrane microdomain can also recruit thrombin to activate the EPCR-bound protein C, thereby eliciting PAR-1 signaling events that are involved in the APC protective pathways. endothelial protein C receptor ͉ protease-activated receptor 1 ͉ thrombin ͉ thrombomodulin

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“…sEPCR is present in normal plasma (ϳ100 ng/ml) (11). It is released from the endothelium by a metalloproteinase (12). A variety of mediators, including interleukin-1, hydrogen peroxide, phorbol esters, and thrombin dramatically increase EPCR shedding from the endothelium.…”

mentioning

confidence: 99%

Disruption of the Endothelial Cell Protein C Receptor Gene in Mice Causes Placental Thrombosis and Early Embryonic Lethality

Crawley

Ferrell

et al. 2002

Journal of Biological Chemistry

Self Cite

131

110

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The endothelial cell protein C receptor (EPCR) is a type 1 transmembrane protein found primarily on endothelium that binds both protein C and activated protein C with similar affinity. EPCR augments the activation of protein C by the thrombin-thrombomodulin complex. To determine the physiological importance of EPCR, we generated EPCR-deficient mice by homologous targeting in embryonic stem cells. Genotyping of progeny obtained from EPCR ؉/؊ interbreeding indicated that EPCR ؊/؊ embryos died on or before embryonic day 10.5 (E10.5). Reverse transcriptase-PCR confirmed the absence of EPCR mRNA in EPCR ؊/؊ embryos. EPCRembryos removed from extra-embryonic membranes and tissues at day E7.5 and cultured in vitro developed beyond E10.5, suggesting a role for EPCR in the normal function of the placenta and/or at the materno-embryonic interface. Immunohistochemistry revealed the lack of EPCR in trophoblast giant cells of EPCR ؊/؊ embryos. These cells, which normally express EPCR, are in direct contact with the maternal circulation and its clotting factors. In EPCR ؊/؊ embryos, greatly increased fibrin deposition was detected around these cells. To prevent this fibrin deposition, EPCR ؉/؊ -crossed female mice received a daily subcutaneous injection of enoxaparin through pregnancy. Although some EPCR ؊/؊ embryos were rescued from midgestational lethality, this regimen yielded no EPCR ؊/؊ pups. We conclude that EPCR is essential for normal embryonic development. Moreover, EPCR plays a key role in preventing thrombosis at the maternal-embryonic interface.

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Metalloproteolytic Release of Endothelial Cell Protein C Receptor

Cited by 178 publications

References 34 publications

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

Disruption of the Endothelial Cell Protein C Receptor Gene in Mice Causes Placental Thrombosis and Early Embryonic Lethality

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