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Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475397/ https://www.ncbi.nlm.nih.gov/pubmed/30944221 http://dx.doi.org/10.1073/pnas.1814409116 |
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author | Allen-Redpath, Keith Aldrovandi, Maceler Lauder, Sarah N. Gketsopoulou, Anastasia Tyrrell, Victoria J. Slatter, David A. Andrews, Robert Watkins, W. John Atkinson, Georgia McNeill, Eileen Gilfedder, Anna Protty, Majd Burston, James Johnson, Sam R. C. Rodrigues, Patricia R. S. Jones, Dylan O. Lee, Regent Handa, Ashok Channon, Keith Obaji, Samya Alvarez-Jarreta, Jorge Krönke, Gerhard Ackermann, Jochen Jenkins, P. Vince Collins, Peter W. O’Donnell, Valerie B. |
author_facet | Allen-Redpath, Keith Aldrovandi, Maceler Lauder, Sarah N. Gketsopoulou, Anastasia Tyrrell, Victoria J. Slatter, David A. Andrews, Robert Watkins, W. John Atkinson, Georgia McNeill, Eileen Gilfedder, Anna Protty, Majd Burston, James Johnson, Sam R. C. Rodrigues, Patricia R. S. Jones, Dylan O. Lee, Regent Handa, Ashok Channon, Keith Obaji, Samya Alvarez-Jarreta, Jorge Krönke, Gerhard Ackermann, Jochen Jenkins, P. Vince Collins, Peter W. O’Donnell, Valerie B. |
author_sort | Allen-Redpath, Keith |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6475397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-64753972019-04-25 Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity Allen-Redpath, Keith Aldrovandi, Maceler Lauder, Sarah N. Gketsopoulou, Anastasia Tyrrell, Victoria J. Slatter, David A. Andrews, Robert Watkins, W. John Atkinson, Georgia McNeill, Eileen Gilfedder, Anna Protty, Majd Burston, James Johnson, Sam R. C. Rodrigues, Patricia R. S. Jones, Dylan O. Lee, Regent Handa, Ashok Channon, Keith Obaji, Samya Alvarez-Jarreta, Jorge Krönke, Gerhard Ackermann, Jochen Jenkins, P. Vince Collins, Peter W. O’Donnell, Valerie B. Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2019-04-16 2019-04-03 /pmc/articles/PMC6475397/ /pubmed/30944221 http://dx.doi.org/10.1073/pnas.1814409116 Text en Copyright © 2019 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | PNAS Plus Allen-Redpath, Keith Aldrovandi, Maceler Lauder, Sarah N. Gketsopoulou, Anastasia Tyrrell, Victoria J. Slatter, David A. Andrews, Robert Watkins, W. John Atkinson, Georgia McNeill, Eileen Gilfedder, Anna Protty, Majd Burston, James Johnson, Sam R. C. Rodrigues, Patricia R. S. Jones, Dylan O. Lee, Regent Handa, Ashok Channon, Keith Obaji, Samya Alvarez-Jarreta, Jorge Krönke, Gerhard Ackermann, Jochen Jenkins, P. Vince Collins, Peter W. O’Donnell, Valerie B. Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title_full | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title_fullStr | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title_full_unstemmed | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title_short | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
title_sort | phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475397/ https://www.ncbi.nlm.nih.gov/pubmed/30944221 http://dx.doi.org/10.1073/pnas.1814409116 |
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