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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rodriguez, A; Yu, M; Gan, J; Phoo, MT; Rani, A; Marsche, G; Guo, Y; Holinstat, M; Schwendeman, A.
Phospholipase A2 Products Influence the Antiplatelet Functions of Synthetic High-Density Lipoproteins.
J Lipid Res. 2025; 100972
Doi: 10.1016/j.jlr.2025.100972
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- Co-Autor*innen der Med Uni Graz
- Marsche Gunther
- RANI Alankrita
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- Abstract:
- Multiple synthetic high-density lipoproteins (sHDLs) have been developed and extensively evaluated in preclinical and clinical trials, with their functionality potentially linked to specific lipid compositions. This study investigates how lipid composition influences sHDL interactions with platelets. We synthesized sHDL particles using ApoA1 mimetic peptide 22A complexed with various lipids (DMPC, POPC, DSPC, DPPC, and SM) differing in chain lengths, saturation levels, and transition temperatures. DMPC sHDL demonstrated superior inhibition of platelet aggregation across multiple agonist concentrations, while POPC sHDL showed limited efficacy only at lower thrombin concentrations. Interestingly, all formulations exhibited similar cholesterol removal abilities, and POPC sHDL demonstrated the highest platelet association despite its inferior antiplatelet effects. Mechanistic investigation revealed the involvement of phospholipase A2 (PLA2) enzymes in DMPC sHDL's potent antiplatelet effects. Inhibition of cytosolic PLA2 (cPLA2) and lipoprotein-associated PLA2 (Lp-PLA2) significantly reduced DMPC sHDL's antiplatelet activity. We demonstrated PLA2-mediated hydrolysis of DMPC sHDL, resulting in bioactive lipid metabolites, lysophosphatidylcholine (LPC) 14:0 and myristic acid, both in vitro and in vivo. These metabolites directly inhibited platelet aggregation, integrin activation, and α-granule secretion in a dose-dependent manner, with significantly greater potency than metabolites derived from other phospholipids. Our findings elucidate a novel mechanism by which sHDL's lipid composition influences its antiplatelet properties through the generation of bioactive lipid metabolites, offering insights for developing targeted cardiovascular therapies.