Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3
Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are prothrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unide...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002323 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582230946349056 |
|---|---|
| author | Majd B. Protty Victoria J. Tyrrell Ali A. Hajeyah Bethan Morgan Daniela Costa Yong Li Anirban Choudhury Rito Mitra David Bosanquet Alex Reed Iuliia K. Denisenko Katsuyuki Nagata Hideo Shindou Benjamin F. Cravatt Alastair W. Poole Takao Shimizu Zaheer Yousef Peter W. Collins Valerie B. O’Donnell |
| author_facet | Majd B. Protty Victoria J. Tyrrell Ali A. Hajeyah Bethan Morgan Daniela Costa Yong Li Anirban Choudhury Rito Mitra David Bosanquet Alex Reed Iuliia K. Denisenko Katsuyuki Nagata Hideo Shindou Benjamin F. Cravatt Alastair W. Poole Takao Shimizu Zaheer Yousef Peter W. Collins Valerie B. O’Donnell |
| author_sort | Majd B. Protty |
| collection | DOAJ |
| description | Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are prothrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unidentified. eoxPL were measured in platelets and leukocytes from an atherosclerotic cardiovascular disease (ASCVD) cohort and retrieved human arterial thrombi from three anatomical sites. The impact of age, gender, and aspirin was characterized in platelets from healthy subjects administered low-dose aspirin. The role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) in eoxPL biosynthesis was tested using an inhibitor and a cell-free assay. Platelets from ASCVD patients generated lower levels of COX-derived eoxPL but elevated 12-LOX-diacyl forms, than platelets from healthy controls. This associated with aspirin and was recapitulated in healthy subjects by aspirin supplementation. P2Y12 inhibition had no impact on eoxPL. LPCAT3 inhibition selectively prevented 12-LOX-derived diacyl-eoxPL generation. LPCAT3 activity was not directly altered by aspirin. P2Y12 inhibition or aspirin had little impact on eoxPL in leukocytes. Complex aspirin-dependent gender and seasonal effects on platelet eoxPL generation were seen in healthy subjects. Limb or coronary (ST-elevation myocardial infarction, STEMI) thrombi displayed a platelet eoxPL signature while carotid thrombi had a white cell profile. EoxPL are altered in ASCVD by a commonly used cardiovascular therapy, and LPCAT3 was identified as the acyltransferase generating aspirin-sensitive 12-LOX diacyl forms. These changes to the phospholipid composition of blood cells in humans at risk of thrombosis may be clinically significant where the procoagulant membrane plays a central role in driving elevated thrombotic risk. |
| format | Article |
| id | doaj-art-5ada54599bd9453ea554de68ce01c8a1 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-5ada54599bd9453ea554de68ce01c8a12025-01-30T05:12:41ZengElsevierJournal of Lipid Research0022-22752025-01-01661100727Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3Majd B. Protty0Victoria J. Tyrrell1Ali A. Hajeyah2Bethan Morgan3Daniela Costa4Yong Li5Anirban Choudhury6Rito Mitra7David Bosanquet8Alex Reed9Iuliia K. Denisenko10Katsuyuki Nagata11Hideo Shindou12Benjamin F. Cravatt13Alastair W. Poole14Takao Shimizu15Zaheer Yousef16Peter W. Collins17Valerie B. O’Donnell18Systems Immunity Research Institute, Cardiff University, Cardiff, UK; For correspondence: Valerie B. O’Donnell; Majd B. ProttySystems Immunity Research Institute, Cardiff University, Cardiff, UKSystems Immunity Research Institute, Cardiff University, Cardiff, UKSystems Immunity Research Institute, Cardiff University, Cardiff, UKSystems Immunity Research Institute, Cardiff University, Cardiff, UKBristol Platelet Group, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UKMorriston Cardiac Centre, Swansea Bay University Health Board, Swansea, UKDepartment of Cardiology, University Hospital of Wales, Cardiff, UKDepartment of Vascular Surgery, Aneurin Bevan University Health Board, Cwmbran, UKDepartment of Chemistry, The Scripps Research Institute, San Diego, CASystems Immunity Research Institute, Cardiff University, Cardiff, UKNational Center for Global Health and Medicine, Tokyo, JapanNational Center for Global Health and Medicine, Tokyo, JapanDepartment of Chemistry, The Scripps Research Institute, San Diego, CABristol Platelet Group, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UKNational Center for Global Health and Medicine, Tokyo, JapanDepartment of Cardiology, University Hospital of Wales, Cardiff, UKSystems Immunity Research Institute, Cardiff University, Cardiff, UKSystems Immunity Research Institute, Cardiff University, Cardiff, UK; For correspondence: Valerie B. O’Donnell; Majd B. ProttyEnzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are prothrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unidentified. eoxPL were measured in platelets and leukocytes from an atherosclerotic cardiovascular disease (ASCVD) cohort and retrieved human arterial thrombi from three anatomical sites. The impact of age, gender, and aspirin was characterized in platelets from healthy subjects administered low-dose aspirin. The role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) in eoxPL biosynthesis was tested using an inhibitor and a cell-free assay. Platelets from ASCVD patients generated lower levels of COX-derived eoxPL but elevated 12-LOX-diacyl forms, than platelets from healthy controls. This associated with aspirin and was recapitulated in healthy subjects by aspirin supplementation. P2Y12 inhibition had no impact on eoxPL. LPCAT3 inhibition selectively prevented 12-LOX-derived diacyl-eoxPL generation. LPCAT3 activity was not directly altered by aspirin. P2Y12 inhibition or aspirin had little impact on eoxPL in leukocytes. Complex aspirin-dependent gender and seasonal effects on platelet eoxPL generation were seen in healthy subjects. Limb or coronary (ST-elevation myocardial infarction, STEMI) thrombi displayed a platelet eoxPL signature while carotid thrombi had a white cell profile. EoxPL are altered in ASCVD by a commonly used cardiovascular therapy, and LPCAT3 was identified as the acyltransferase generating aspirin-sensitive 12-LOX diacyl forms. These changes to the phospholipid composition of blood cells in humans at risk of thrombosis may be clinically significant where the procoagulant membrane plays a central role in driving elevated thrombotic risk.http://www.sciencedirect.com/science/article/pii/S0022227524002323lipidomicsthrombosisphospholipidsacute coronary syndromeplatelets |
| spellingShingle | Majd B. Protty Victoria J. Tyrrell Ali A. Hajeyah Bethan Morgan Daniela Costa Yong Li Anirban Choudhury Rito Mitra David Bosanquet Alex Reed Iuliia K. Denisenko Katsuyuki Nagata Hideo Shindou Benjamin F. Cravatt Alastair W. Poole Takao Shimizu Zaheer Yousef Peter W. Collins Valerie B. O’Donnell Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 Journal of Lipid Research lipidomics thrombosis phospholipids acute coronary syndrome platelets |
| title | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 |
| title_full | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 |
| title_fullStr | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 |
| title_full_unstemmed | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 |
| title_short | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3 |
| title_sort | aspirin modulates generation of procoagulant phospholipids in cardiovascular disease by regulating lpcat3 |
| topic | lipidomics thrombosis phospholipids acute coronary syndrome platelets |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002323 |
| work_keys_str_mv | AT majdbprotty aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT victoriajtyrrell aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT aliahajeyah aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT bethanmorgan aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT danielacosta aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT yongli aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT anirbanchoudhury aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT ritomitra aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT davidbosanquet aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT alexreed aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT iuliiakdenisenko aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT katsuyukinagata aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT hideoshindou aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT benjaminfcravatt aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT alastairwpoole aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT takaoshimizu aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT zaheeryousef aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT peterwcollins aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 AT valeriebodonnell aspirinmodulatesgenerationofprocoagulantphospholipidsincardiovasculardiseasebyregulatinglpcat3 |