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Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome

Artim-Esen, B; Smoktunowicz, N; McDonnell, T; Ripoll, VM; Pericleous, C; Mackie, I; Robinson, E; ... Giles, I; + view all (2017) Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome. Scientific Reports , 7 (1) , Article 10788. 10.1038/s41598-017-11315-9. Green open access

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Abstract

Factor (F) Xa reactive IgG isolated from patients with antiphospholipid syndrome (APS) display higher avidity binding to FXa with greater coagulant effects compared to systemic lupus erythematosus (SLE) non APS IgG. FXa signalling via activation of protease-activated receptors (PAR) leads to increased intracellular calcium (Ca(2+)). Therefore, we measured alterations in Ca(2+) levels in human umbilical vein endothelial cells (HUVEC) following FXa-mediated PAR activation and investigated whether FXa reactive IgG from patients with APS or SLE/APS- alter these responses. We observed concentration-dependent induction of Ca(2+) release by FXa that was potentiated by APS-IgG and SLE/APS- IgG compared to healthy control subjects' IgG, and FXa alone. APS-IgG and SLE/APS- IgG increased FXa mediated NFκB signalling and this effect was fully-retained in the affinity purified anti-FXa IgG sub-fraction. Antagonism of PAR-1 and PAR-2 reduced FXa-induced Ca(2+) release. Treatment with a specific FXa inhibitor, hydroxychloroquine or fluvastatin significantly reduced FXa-induced and IgG-potentiated Ca(2+) release. In conclusion, PAR-1 and PAR-2 are involved in FXa-mediated intracellular Ca(2+) release in HUVEC and FXa reactive IgG from patients with APS and/or SLE potentiate this effect. Further work is required to explore the potential use of IgG FXa reactivity as a novel biomarker to stratify treatment with FXa inhibitors in these patients.

Type: Article
Title: Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-017-11315-9
Publisher version: http://dx.doi.org/10.1038/s41598-017-11315-9
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Rheumatology, Systemic lupus erythematosus
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1573184
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