TY - JOUR
T1 - Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity
AU - Allen-Redpath, Keith
AU - Aldrovandi, Maceler
AU - Lauder, Sarah N.
AU - Gketsopoulou, Anastasia
AU - Tyrrell, Victoria J.
AU - Slatter, David A.
AU - Andrews, Robert
AU - John Watkins, W.
AU - Atkinson, Georgia
AU - McNeill, Eileen
AU - Gilfedder, Anna
AU - Protty, Majd
AU - Burston, James
AU - Johnson, Sam R.C.
AU - Rodrigues, Patricia R.S.
AU - Jones, Dylan O.
AU - Lee, Regent
AU - Handa, Ashok
AU - Channon, Keith
AU - Obaji, Samya
AU - Alvarez-Jarreta, Jorge
AU - Krönke, Gerhard
AU - Ackermann, Jochen
AU - Vince Jenkins, P.
AU - Collins, Peter W.
AU - O’Donnell, Valerie B.
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/4/16
Y1 - 2019/4/16
N2 - 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.
AB - 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.
KW - Aneurysm
KW - Angiotensin
KW - Lipid
KW - Lipoxygenase
KW - Phospholipid
UR - https://www.scopus.com/pages/publications/85064402006
U2 - 10.1073/pnas.1814409116
DO - 10.1073/pnas.1814409116
M3 - Article (Academic Journal)
C2 - 30944221
AN - SCOPUS:85064402006
SN - 0027-8424
VL - 116
SP - 8038
EP - 8047
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -
