Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3.

Protty, Majd B., Tyrrell, Victoria J., Hajeyah, Ali A., Morgan, Bethan, Costa, Daniela ORCID: https://orcid.org/0000-0001-8821-5898, Li, Yong, Choudhury, Anirban, Mitra, Rito, Bosanquet, David, Reed, Alex, Denisenko, Iuliia K, Nagata, Katsuyuki, Shindou, Hideo, Cravatt, Benjamin F., Poole, Alastair W., Shimizu, Takao, Yousef, Zaheer, Collins, Peter W. ORCID: https://orcid.org/0000-0002-6410-1324 and O'Donnell, Valerie B ORCID: https://orcid.org/0000-0003-4089-8460 2025. Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3. Journal of Lipid Research 66 (1) , 100727. 10.1016/j.jlr.2024.100727

PDF - Published Version Available under License Creative Commons Attribution. Download (5MB)

Abstract

Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are pro-thrombotic. 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 3 anatomical sites. The impact of age, gender and aspirin was characterized in platelets from healthy subjects administered low-dose aspirin. The role of 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 (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 pro-coagulant membrane plays a central role in driving elevated thrombotic risk. [Abstract copyright: Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.]

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0022-2275
Date of First Compliant Deposit:	13 January 2025
Date of Acceptance:	10 December 2024
Last Modified:	16 Jan 2025 14:07
URI:	https://orca.cardiff.ac.uk/id/eprint/175227

Actions (repository staff only)

Edit Item