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DC Field | Value | Language |
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dc.contributor.author | Allen-Redpath, K | - |
dc.contributor.author | Aldrovandi, M | - |
dc.contributor.author | Lauder, SN | - |
dc.contributor.author | Gketsopoulou, A | - |
dc.contributor.author | Tyrrell, VJ | - |
dc.contributor.author | Slatter, DA | - |
dc.contributor.author | Andrews, R | - |
dc.contributor.author | John Watkins, W | - |
dc.contributor.author | Atkinson, G | - |
dc.contributor.author | McNeill, E | - |
dc.contributor.author | Gilfedder, A | - |
dc.contributor.author | Protty, M | - |
dc.contributor.author | Burston, J | - |
dc.contributor.author | Johnson, SRC | - |
dc.contributor.author | Rodrigues, PRS | - |
dc.contributor.author | Jones, DO | - |
dc.contributor.author | Lee, R | - |
dc.contributor.author | Handa, A | - |
dc.contributor.author | Channon, K | - |
dc.contributor.author | Obaji, S | - |
dc.contributor.author | Alvarez-Jarreta, J | - |
dc.contributor.author | Krönke, G | - |
dc.contributor.author | Ackermann, J | - |
dc.contributor.author | Vince Jenkins, P | - |
dc.contributor.author | Collins, PW | - |
dc.contributor.author | O’Donnell, VB | - |
dc.date.accessioned | 2023-04-08T10:35:14Z | - |
dc.date.available | 2023-04-08T10:35:14Z | - |
dc.date.issued | 2019-04-03 | - |
dc.identifier | ORCID iD: Keith Allen-Redpath https://orcid.org/0009-0004-7213-2675 | - |
dc.identifier | ORCID iD: Valerie B. O’Donnell https://orcid.org/0000-0003-4089-8460 | - |
dc.identifier.citation | Allen-Redpath, K. et al. (2019) 'Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity', Proceedings of the National Academy of Sciences of the United States of America, 116 (16), pp. 8038 - 8047. doi: 10.1073/pnas.1814409116. | en_US |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/26257 | - |
dc.description | Supporting Information: Appendix (PDF) available online at: https://www.pnas.org/doi/suppl/10.1073/pnas.1814409116/suppl_file/pnas.1814409116.sapp.pdf . | en_US |
dc.description.abstract | Copyright © The Authors 2019. Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE−/− mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE−/− deletion, and many were absent in Alox−/− mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development. | en_US |
dc.description.sponsorship | Funding is acknowledged from Wellcome Trust Programme Grant (094143/Z/10/Z), British Heart Foundation Programme Grant (RG/12/11/29815), and European Research Council Advanced Grant (LipidArrays) (to V.B.O.). V.B.O. is a Royal Society Wolfson Research Merit Award Holder and acknowledges funding for LIPID MAPS from the Wellcome Trust Grant (203014/Z/16/Z). This work was supported by the Oxford British Heart Foundation (BHF) Centre of Research Excellence Award (RG/13/1/30181), BHF Chair Award (CH/16/1/32013), and BHF Programme Grant (RG/15/10/31485). S.O. holds a British Heart Foundation Clinical Research Fellowship (FS/16/20/32005). M.P. is a GW4-CAT Wellcome Trust Clinical Fellow. Oxford Abdominal Aortic Aneurysm Study and Oxford Regional Vascular Services are acknowledged. R.L. received grant funding from the Academy of Medical Sciences (SGL013/1015). | en_US |
dc.format.extent | 8038 - 8047 | - |
dc.format.medium | Print-Electronic | - |
dc.language.iso | en_US | en_US |
dc.publisher | National Academy of Science | en_US |
dc.rights | Copyright © The Authors 2019. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | aneurysm | en_US |
dc.subject | lipid | en_US |
dc.subject | phospholipid | en_US |
dc.subject | lipoxygenase | en_US |
dc.subject | angiotensin | en_US |
dc.title | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.1073/pnas.1814409116 | - |
dc.relation.isPartOf | Proceedings of the National Academy of Sciences of the United States of America | - |
pubs.issue | 16 | - |
pubs.publication-status | Published | - |
pubs.volume | 116 | - |
dc.identifier.eissn | 1091-6490 | - |
dc.rights.holder | The Authors | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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File | Description | Size | Format | |
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FullText.pdf | Copyright © The Authors 2019. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) | 2.01 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License