Endothelial cell protein C receptor plays an important role in protein C activation in vivo

Taylor, Fletcher B.; Peer, G.; Lockhart, Marion S.; Ferrell, Gary; Esmon, Charles T.

doi:10.1182/blood.v97.6.1685

Cited by 253 publications

(160 citation statements)

References 18 publications

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“…7,8 In vivo, blocking protein C-EPCR interactions results in an 88% decrease in circulating APC levels generated in response to thrombin infusion. 9 EPCR function is critical for embryo development because EPCR knockout mice die in midgestation. 10 The normal distribution of EPCR is highly tissue specific.…”

Section: Introductionmentioning

confidence: 99%

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Mollica

Crawley

Liu

et al. 2006

Blood

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The endothelial cell protein C receptor (EPCR) is expressed by endothelial cells of large blood vessels and by hematopoietic stem cells. DNaseI hypersensitive (DH) site mapping across 38 kb of the human EPCR gene (hEPCR) locus identified 3 potential regulatory elements. By itself, the DH region spanning the proximal promoter (PP) was unable to direct cell-specific transcription in transgenic mice. A second DH element, located upstream of PP and termed ؊5.5HS was hypersensitive only in endothelial cells (ECs) and immature hematopoietic cell lines. Transgenes expressing LacZ under the control of ؊5.5HS coupled to either PP or the SV40 promoter were able to direct ␤-galactosidase activity to the endothelium of large vessels during embryogenesis and adulthood. The ؊5.5HS exhibited enhancer activity that was conferred by the interplay of transcription factors interacting with conserved Ets and composite GATA/Tal1 motifs. The third DH element, located in intron 2, was primarily hypersensitive in EPCR-negative cells, and capable of initiating antisense transcription, suggesting a role in hEPCR silencing. This study identifies critical elements required for the tissue specificity of hEPCR and suggests a mechanism for endothelial and hematopoietic stem cell-specific transcriptional regulation that reflects the common origin of these cell types. IntroductionThe protein C (PC) anticoagulant pathway plays a crucial role in the regulation of blood coagulation and inflammation. 1 Activated PC (APC) generated in this pathway serves to confine the hemostatic plug to the site of vascular injury by inhibiting the cofactor function of clotting factors Va and VIIIa on intact endothelium. In addition, APC may also exert antiapoptotic and neuroprotective functions that influence inflammatory responses. 2,3 The important regulatory roles of APC in coagulation and inflammation are illustrated by the increased risk of thrombosis incurred by individuals with deficiencies in components of the PC pathway 4 and by the improved outcome of patients with severe sepsis treated with APC. 5 PC is activated by thrombin, but only when thrombin is bound to its receptor, thrombomodulin, present on endothelial cells (ECs). Activation is further enhanced by another EC receptor, the endothelial cell protein C receptor (EPCR). 6 By binding PC, EPCR helps present PC to the thrombin:thrombomodulin complex and so reduces the K m for PC activation. 7 In this way, EPCR enhances APC generation by at least 5-fold in vitro. 7,8 In vivo, blocking protein C-EPCR interactions results in an 88% decrease in circulating APC levels generated in response to thrombin infusion. 9 EPCR function is critical for embryo development because EPCR knockout mice die in midgestation. 10 The normal distribution of EPCR is highly tissue specific. During embryogenesis, EPCR is expressed by the embryonic giant trophoblast cells from approximately E7.5, and by certain embryonic EC from approximately E11.5. 11 In adults, EPCR is expressed almost exclusively by ECs, particularly those o...

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Section: Introductionmentioning

confidence: 99%

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Mollica

Crawley

Liu

et al. 2006

Blood

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“…Thus, virtually all recently reported mixed chimerism protocols involve anti-CD40L [8,14,18,19]. As long as no effective anti-CD40L mAb is available for clinical use, its elimination from recipient conditioning would be desirable.…”

Section: Experimental Protocols Minimizing Conditioning Avoiding Globmentioning

confidence: 99%

“…While some form of (local) irradiation was universally required even when very profound doses of T-cell depleting antibodies (anti-CD4 and anti-CD8 mAb) were given as part of the conditioning [9,10], costimulation blockade allowed the elimination of any irradiation from recipient conditioning if very high doses (mega doses) of allogeneic BM were transplanted [7,11]. Anti-CD40L is sufficiently effective alone (without CTLA4Ig) in strain combinations without minor antigen barriers (e.g., donor B10.A → recipient C57BL/10) [12,13] [8,14,18,19]. As long as no effective anti-CD40L mAb is available for clinical use, its elimination from recipient conditioning would be desirable.…”

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confidence: 99%

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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“…Binding of PC to its endothelial receptor, EPCR, accelerates PC activation by the thrombin-thrombomodulin complex. 25 The third known clotting factor inhibitor is TF pathway inhibitor, which inactivates the TF-FVIIa complex after formation of a quaternary complex with FXa. 26 More recently, a new vitamin K dependent factor Xa inhibitor, protein Z, has been described.…”

Section: Ii-2-the Physiology Of Coagulationmentioning

confidence: 99%

From normal to pathological hemostasis

Lasne

Jude

Susen

2006

Can J Anesth/J Can Anesth

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Purpose:To review the evolution of knowledge on physiological hemostasis and the main abnormalities that may interfere with hemostasis in the perioperative period.Methods: Narrative review of the literature, including relevant papers published in English.Principal findings: Physiological hemostasis controls blood fluidity and rapidly induces hemostatic plug formation in order to stop or limit bleeding. The three distinct phases of the hemostatic process, primary hemostasis, coagulation and fibrinolysis are closely linked to each other and precisely regulated in order to efficiently close vessel wounds, promote vascular healing and maintain vessel patency. Primary hemostasis is the result of complex interactions between the vascular wall, platelets and adhesive proteins. Initiation of the coagulation pathway in vivo is secondary to the exposure of tissue factor (TF) and the formation of TF/VIIa complex which can activate both FIX and FX. This initiation phase is followed by a propagation phase with amplification of thrombin generation. Several control mechanisms exist for localizing fibrin formation to the site of injury including tissue factor pathway inhibitor, protein C system, antithrombin, and glycosaminoglycans on the vessel wall. Fibrinolysis is also a highly regulated system that controls fibrin dissolution. Both constitutive and acquired hemostasic defects exist. The consequences of these abnormalities are highly variable according to the type of defect, and to the genetic and environmental background. Conclusion:Hemostasis is one of the most complex physiological self-defence systems, not only involved in control of blood fluidity but also interfering in major physiopathological processes. The evolution of our knowledge of the physiology of hemostasis has numerous implications for therapy. P HYSIOLOGICAL hemostasis is a highly adaptative process that controls blood fluidity, and rapidly induces hemostatic plug formation after vascular injury, in order to stop or limit bleeding. After an initial triggering event, sequential steps occur, including a complex cascade of clotting factor and platelet activation. Red blood cells, leukocytes and endothelial cells are also involved in the propagation and the regulation of clot formation. The three distinct phases of the hemostatic process are pri- From normal to pathological hemostasis [De l'hémostase normale à l'hémostase pathologique] Objectif

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Endothelial cell protein C receptor plays an important role in protein C activation in vivo

Cited by 253 publications

References 18 publications

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

From normal to pathological hemostasis

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