Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity
| العنوان: | Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity |
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| المؤلفون: | Allen-Redpath, K, Aldrovandi, M, Lauder, SN, Gketsopoulou, A, Tyrrell, VJ, Slatter, DA, Andrews, R, Watkins, WJ, Atkinson, G, McNeill, E, Gilfedder, A, Protty, M, Burston, J, Johnson, SRC, Rodrigues, PRS, Jones, DO, Lee, R, Handa, A, Channon, K, Obaji, S, Alvarez-Jarreta, J, Krönke, G, Ackermann, J, Jenkins, PV, Collins, PW, O'Donnell, VB |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, Angiotensins, Physiology, Mice, Knockout, ApoE, Lipoxygenase, Biological Sciences, angiotensin, lipoxygenase, Blood Coagulation Factors, Disease Models, Animal, Mice, PNAS Plus, lipid, cardiovascular system, aneurysm, Animals, Female, cardiovascular diseases, Aorta, Abdominal, phospholipid, Phospholipids, Aortic Aneurysm, Abdominal |
| الوصف: | Significance Abdominal aortic aneurysm (AAA) is a disease of the abdominal aorta where inflammation causes damage and can ultimately lead to rupture. When this happens, uncontrolled internal bleeding can lead to death within minutes. Many aneurysms are not detected until they rupture, and for those that are, treatments to stop them progressing are limited. Here we used biophysics and genetically modified mice to show that a new family of lipids (fats) made by circulating blood cells promote AAA formation in the vessel wall because they directly regulate blood clotting. An approach that prevents AAA development was identified, based on intravenous administration of lipids. The studies provide insights into how AAA develops and may lead to novel therapies for this disease. 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. |
| وصف الملف: | Print-Electronic; application/pdf |
| اللغة: | English |
| تدمد: | 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::c578070775aca45439d10f8ed4410bfaTest https://ora.ox.ac.uk/objects/uuid:9a217d97-a4d3-4fa5-9ce7-63b306358451Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....c578070775aca45439d10f8ed4410bfa |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00278424 |
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