Multiple receptor-mediated functions of activated protein C

2011 ◽  
Vol 31 (03) ◽  
pp. 185-195 ◽  
Author(s):  
H. Weiler
Keyword(s):  
Protein C ◽  
Cell Function ◽  
Immune Cell ◽  
Current Knowledge ◽  
Activated Protein C ◽  
Biological Response ◽  
Cell Protein ◽  
Protease Activated Receptors ◽  
Tissue Factor Pathway ◽  
Biologic Function

SummaryThe central effector protease of the protein C pathway, activated protein C (APC), interacts with the endothelial cell protein C receptor, with protease activated receptors (PAR), the apolipoprotein E2 receptor, and integrins to exert multiple effects on haemostasis and immune cell function. Such receptor interactions modify the activation of PC and determine the biological response to endogenous and therapeutically administered APC. This review summarizes the current knowledge about interactions of APC with cell surface-associated receptors, novel substrates such as histones and tissue factor pathway inhibitor, and their implications for the biologic function of APC in the control of coagulation and inflammation.

scholarly journals Identification of the Protein C/Activated Protein C Binding Sites on the Endothelial Cell Protein C Receptor

2000 ◽  
Vol 276 (11) ◽  
pp. 8364-8370 ◽  
Author(s):  
Patricia C. Y. Liaw ◽  
Timothy Mather ◽  
Natalia Oganesyan ◽  
Gary L. Ferrell ◽  
Charles T. Esmon
Keyword(s):  
Endothelial Cell ◽  
Binding Sites ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein

scholarly journals Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor

2003 ◽  
Vol 373 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Laurent O. MOSNIER ◽  
John H. GRIFFIN
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Active Site ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein ◽  
Protease Activated Receptor 1 ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Dose Dependent

In a model of staurosporine-induced apoptosis using EAhy926 endothelial cells, inhibition of apoptosis by activated protein C was dose-dependent and required the enzyme's active site, implicating activated protein C-mediated proteolysis. Consistent with this implication, both protease-activated receptor-1 (PAR-1) and endothelial cell protein C receptor (EPCR) were required for the anti-apoptotic effects of activated protein C.

Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1

2005 ◽  
Vol 93 (04) ◽  
pp. 743-750 ◽  
Author(s):  
Sarah Horn ◽  
Siegfried Lang ◽  
Kenji Fukudome ◽  
Adriane Nahrup ◽  
Ursula Hoffmann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein ◽  
Mrna Levels ◽  
Endothelial Protein C Receptor ◽  
Drotrecogin Alfa Activated ◽  
Cox 2 ◽  
Vitro Effect

SummaryProstacyclin (PGI2) has beneficial cytoprotective properties, is a potent inhibitor of platelet aggregation and has been reported to improve microcirculatory blood flow during sepsis. The formation of PGI2 in response to proinflammatory cytokines is catalysed by the inducible cyclooxygenase (COX) isoform COX-2. Recombinant human activated protein C (rhAPC, drotrecogin alfa (activated)) was shown to have multiple biological activities in vitro and to promote resolution of organ dysfunction in septic patients. Whether rhAPC exerts its beneficial effects by modulating prostanoid generation is unknown up to now. It was therefore the aim of the study to examine the in vitro effect of rhAPC on COX-2-mRNA-expression and PGI2 release from human umbilical vein endothelial cells (HUVEC). We found that rhAPC, at supra-therapeutical concentrations (500ng/ml-20μg/ ml), upregulated the amount of COX-2-mRNA in HUVEC at t=3–9h and caused a time- and dose-dependent release of 6-keto PGF1α, the stable hydrolysis product of prostacyclin. RhAPC further increased the stimulating effect of tumor necrosis factor-α (TNF-α) and thrombin on COX-2-mRNA-levels. Transcript levels of cyclooxygenase-1 (COX-1) and prostagland-in I2 synthase, however, were unaffected by the stimulation with rhAPC or thrombin. The upregulatory effect on COX2-mRNA levels was specific for rhAPC since the zymogen protein C in equimolar concentrations had no effect on COX-2-mRNA-levels or 6keto PGF1α-release. Western Blot analysis revealed an increase of COX-2-protein content in HUVEC after treatment with rhAPC. As shown by experiments using monoclonal antibodies against the thrombin receptor PAR-1 (mAb=ATAP2) and against the endothelial protein C receptor (EPCR; mAb=RCR-252), the effect of rhAPC on COX-2-mRNA up-regulation was mediated by binding to the EPCR-receptor and signaling via PAR-1. These results demonstrate that induction of COX-2-expression is an important response of HUVEC to stimulation with rhAPC and may represent a new molecular mechanism, by which rhAPC promotes upregulation of prostanoid production in human endothelium.

scholarly journals Activated Protein C Prevents Neuronal Apoptosis via Protease Activated Receptors 1 and 3

Neuron ◽  
2004 ◽  
Vol 41 (4) ◽  
pp. 563-572 ◽  
Author(s):  
Huang Guo ◽  
Dong Liu ◽  
Harris Gelbard ◽  
Tong Cheng ◽  
Rae Insalaco ◽  
...  
Keyword(s):  
Protein C ◽  
Neuronal Apoptosis ◽  
Activated Protein C ◽  
Protease Activated Receptors

Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk

2004 ◽  
Vol 91 (05) ◽  
pp. 905-911 ◽  
Author(s):  
Pilar Medina ◽  
Silvia Navarro ◽  
Amparo Estellés ◽  
Amparo Vayá ◽  
Barry Woodhams ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Receptor Gene ◽  
Activated Protein C ◽  
Soluble Form ◽  
Cell Protein ◽  
Endothelial Protein C Receptor ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
The Relationship

SummaryEndothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3’-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.

Patients with severe sepsis vary markedly in their ability to generate activated protein C

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 3958-3964 ◽  
Author(s):  
Patricia C. Y. Liaw ◽  
Charles T. Esmon ◽  
Kamyar Kahnamoui ◽  
Shelley Schmidt ◽  
Sarah Kahnamoui ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Cell Protein ◽  
Health Evaluation ◽  
On Demand ◽  
Evaluation Scores ◽  
Plasma Markers

Abstract Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) “on demand” in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis. (Blood. 2004;104:3958-3964)

scholarly journals Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 585-591 ◽  
Author(s):  
Rashmi Sood ◽  
Lynette Sholl ◽  
Berend Isermann ◽  
Mark Zogg ◽  
Shaun R. Coughlin ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Fetal Loss ◽  
Trophoblast Cells ◽  
Protease Activated Receptors ◽  
Genetic Ablation ◽  
Coagulation Inhibitor ◽  
Placental Failure ◽  
New Evidence

Abstract Absence of the blood coagulation inhibitor thrombomodulin (Thbd) from trophoblast cells of the mouse placenta causes a fatal arrest of placental morphogenesis. The pathogenesis of placental failure requires tissue factor, yet is not associated with increased thrombosis and persists in the absence of fibrinogen. Here, we examine the role of alternative targets of coagulation that might contribute to the placental failure and death of Thbd−/− embryos. We demonstrate that genetic deficiency of the protease-activated receptors, Par1 or Par2, in the embryo and trophoblast cells does not prevent the death of Thbd−/− embryos. Similarly, genetic ablation of the complement pathway or of maternal immune cell function does not decrease fetal loss. In contrast, Par4 deficiency of the mother, or the absence of maternal platelets, restores normal development in one-third of Thbd-null embryos. This finding generates new evidence implicating increased procoagulant activity and thrombin generation in the demise of thrombomodulin-null embryos, and suggests that platelets play a more prominent role in placental malfunction associated with the absence of thrombomodulin than fibrin formation. Our findings demonstrate that fetal prothrombotic mutations can cause localized activation of maternal platelets at the feto-maternal interface in a mother with normal hemostatic function.

Is EPCR a multi-ligand receptor? Pros and cons

2012 ◽  
Vol 107 (05) ◽  
pp. 815-826 ◽  
Author(s):  
Eva Molina ◽  
José Hermida ◽  
Ramón Montes ◽  
Cristina Puy
Keyword(s):  
Serine Proteases ◽  
Protein C ◽  
Cell Signalling ◽  
Activated Protein C ◽  
Factor Xa ◽  
Factor Vii ◽  
Cell Protein ◽  
Tissue Remodelling ◽  
Healing Tissue ◽  
Dependent Cell

SummaryIn the last decade, the endothelial cell protein C/activated protein C receptor (EPCR) has received considerable attention. The role initially attributed to EPCR, i.e. the enhancement of protein C (PC) activation by the thrombin-thrombomodulin complex on the surface of the large vessels, although important, did not go beyond the haemostasis scenario. However, the discovery of the cytoprotective, anti-inflammatory and anti-apoptotic features of the activated PC (APC) and the required involvement of EPCR for APC to exert such actions did place the receptor in a privileged position in the crosstalk between coagulation and inflammation. The last five years have shown that PC/APC are not the only molecules able to interact with EPCR. Factor VII/VIIa (FVII/VIIa) and factor Xa (FXa), two other serine proteases that play a central role in haemostasis and are also involved in signalling processes influencing wound healing, tissue remodelling, inflammation or metastasis, have been reported to bind to EPCR. These observations have paved the way for an exploration of unsuspected new roles for the receptor. This review aims to offer a new image of EPCR in the light of its extended panel of ligands. A brief update of what is known about the APC-evoked EPCR-dependent cell signalling mechanisms is provided, but special care has been taken to assemble all the information available about the interaction of EPCR with FVII/VIIa and FXa.

scholarly journals Histone Deacetylases in the Inflamed Intestinal Epithelium—Promises of New Therapeutic Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Lorenz Gerbeth ◽  
Rainer Glauben
Keyword(s):  
Cell Signaling ◽  
Intestinal Epithelium ◽  
Histone Deacetylases ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Therapeutic Approaches ◽  
Inflammatory Conditions

The intestinal epithelium is a complex, dynamic barrier that separates luminal contents from the immune compartment while mediating nutrient absorption and controlled passage of antigens to convey oral tolerance. A compromised epithelial barrier often leads to inflammation because immune cells in the lamina propria come into direct contact with luminal antigens. Defects in epithelial cell function were also shown to be involved in the etiology of inflammatory bowel diseases. These are severe, chronically relapsing inflammatory conditions of the gastrointestinal tract that also increase the risk of developing colorectal cancer. Despite major efforts of the scientific community, the precise causes and drivers of these conditions still remain largely obscured impeding the development of a permanent cure. Current therapeutic approaches mostly focus on alleviating symptoms by targeting immune cell signaling. The protein family of histone deacetylases (HDACs) has gained increasing attention over the last years, as HDAC inhibitors were shown to be potent tumor cell suppressors and also alleviate morbid inflammatory responses. Recent research continuously identifies new roles for specific HDACs suggesting that HDACs influence the cell signaling network from many different angles. This makes HDACs very interesting targets for therapeutic approaches but predicting effects after system manipulations can be difficult. In this review, we want to provide a comprehensive overview of current knowledge about the individual roles of HDACs in the intestinal epithelium to evaluate their therapeutic potential for inflammatory conditions of the gut.

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