Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: 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
Zeitschrift: Proceedings of the National Academy of Sciences of the United States of America
Jahr der Veröffentlichung: 2019
Band: 116
Heftnummer: 16
Seitenbereich: 8038-8047
ISSN: 0027-8424
eISSN: 1091-6490


Abstract

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

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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

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deletion, and many were absent in Alox

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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.


FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Krönke, Gerhard Prof. Dr. med.
Professur für Translationale Immunologie


Einrichtungen weiterer Autorinnen und Autoren

Cardiff and Vale University Health Board
Cardiff University
University of Oxford


Zitierweisen

APA:
Allen-Redpath, K., Aldrovandi, M., Lauder, S.N., Gketsopoulou, A., Tyrrell, V.J., Slatter, D.A.,... O'Donnell, V.B. (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), 8038-8047. https://dx.doi.org/10.1073/pnas.1814409116

MLA:
Allen-Redpath, Keith, et al. "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 (2019): 8038-8047.

BibTeX: 

Zuletzt aktualisiert 2019-06-08 um 09:08