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Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3
Majd B Protty1, Victoria J Tyrrell1, Ali A Hajeyah1
1Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
Insights
Enzymatically oxygenated phospholipids (eoxPL) are prothrombotic and altered in atherosclerotic cardiovascular disease (ASCVD). Lysophosphatidylcholine acyltransferase 3 (LPCAT3) generates aspirin-sensitive eoxPL, impacting thrombosis risk.
Area of Science:
- Cardiovascular Research
- Lipid Metabolism
- Thrombosis Biology
Background:
- Enzymatically oxygenated phospholipids (eoxPL) are prothrombotic but their role in arterial disease and response to therapy is unknown.
- The specific acyl-transferases responsible for eoxPL formation via the Lands cycle remain unidentified.
- Understanding eoxPL generation is crucial for managing cardiovascular disease (CVD) and thrombosis risk.
Purpose of the Study:
- To investigate eoxPL generation in atherosclerotic cardiovascular disease (ASCVD) patients and human arterial thrombi.
- To determine the impact of cardiovascular therapies, including aspirin, on eoxPL levels.
- To identify the acyl-transferase responsible for specific eoxPL biosynthesis.
Main Methods:
- Quantification of eoxPL in platelets and leukocytes from ASCVD patients and healthy controls.
- Analysis of eoxPL in human arterial thrombi from different anatomical sites.
- Inhibition studies using a lysophosphatidylcholine acyltransferase 3 (LPCAT3) inhibitor and cell-free assays.
- Assessment of aspirin's impact on eoxPL in healthy subjects.
Main Results:
- ASCVD patients showed altered platelet eoxPL profiles, with lower COX-derived and higher 12-LOX-diacyl eoxPL compared to controls.
- Aspirin supplementation in healthy subjects recapitulated the altered eoxPL profile observed in ASCVD patients.
- LPCAT3 inhibition selectively blocked 12-LOX-derived diacyl-eoxPL, identifying it as the key acyl-transferase.
- Platelet eoxPL signatures differed between limb/coronary thrombi and carotid thrombi.
Conclusions:
- EoxPL levels and composition are significantly altered in ASCVD and influenced by aspirin therapy.
- Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is identified as the acyl-transferase responsible for generating aspirin-sensitive 12-LOX-derived diacyl-eoxPL.
- These findings highlight the clinical significance of eoxPL alterations in blood cells for individuals at risk of thrombosis.
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.
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