Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3.
| Title: | Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3. |
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| Authors: | Protty MB; Systems Immunity Research Institute, Cardiff University, Cardiff, UK. Electronic address: prottym3@cardiff.ac.uk.; Tyrrell VJ; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; Hajeyah AA; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; Morgan B; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; Costa D; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; Li Y; Bristol Platelet Group, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.; Choudhury A; Morriston Cardiac Centre, Swansea Bay University Health Board, Swansea, UK.; Mitra R; Department of Cardiology, University Hospital of Wales, Cardiff, UK.; Bosanquet D; Department of Vascular Surgery, Aneurin Bevan University Health Board, Cwmbran, UK.; Reed A; Department of Chemistry, The Scripps Research Institute, San Diego, CA.; Denisenko IK; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; Nagata K; National Center for Global Health and Medicine, Tokyo, Japan.; Shindou H; National Center for Global Health and Medicine, Tokyo, Japan.; Cravatt BF; Department of Chemistry, The Scripps Research Institute, San Diego, CA.; Poole AW; Bristol Platelet Group, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.; Shimizu T; National Center for Global Health and Medicine, Tokyo, Japan.; Yousef Z; Department of Cardiology, University Hospital of Wales, Cardiff, UK.; Collins PW; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.; O'Donnell VB; Systems Immunity Research Institute, Cardiff University, Cardiff, UK. Electronic address: o-donnellvb@cardiff.ac.uk. |
| Source: | Journal of lipid research [J Lipid Res] 2025 Jan; Vol. 66 (1), pp. 100727. Date of Electronic Publication: 2024 Dec 12. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2021- : [New York] : Elsevier; Original Publication: Memphis, Lipid Research, inc. |
| MeSH Terms: | Aspirin*/pharmacology ; Aspirin*/therapeutic use ; 1-Acylglycerophosphocholine O-Acyltransferase*/metabolism ; Phospholipids*/biosynthesis ; Phospholipids*/metabolism ; Cardiovascular Diseases*/metabolism ; Cardiovascular Diseases*/drug therapy ; Cardiovascular Diseases*/blood ; Cardiovascular Diseases*/pathology; Blood Platelets/metabolism ; Blood Platelets/drug effects ; Leukocytes/metabolism ; Leukocytes/drug effects ; Humans ; Male ; Female ; Middle Aged ; Aged ; Adult |
| Abstract: | 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.; (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Conflict of interest P. C. receives research funding from CSL Behring, Haemonetics Corp, Werfen, and consultancy from CSL Behring. The other authors declare that they have no conflicts of interest with the contents of this article. |
| Grant Information: | United Kingdom WT_ Wellcome Trust; R01 DA033760 United States DA NIDA NIH HHS; RG/F/20/110020 United Kingdom BHF_ British Heart Foundation |
| Contributed Indexing: | Keywords: acute coronary syndrome; lipidomics; phospholipids; platelets; thrombosis |
| Substance Nomenclature: | R16CO5Y76E (Aspirin); EC 2.3.1.23 (1-Acylglycerophosphocholine O-Acyltransferase); 0 (Phospholipids); EC 2.3.1.23 (LPCAT3 protein, human) |
| Entry Date(s): | Date Created: 20241214 Date Completed: 20250427 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11754521 |
| DOI: | 10.1016/j.jlr.2024.100727 |
| PMID: | 39674322 |
| Database: | MEDLINE |
Journal Article