Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 45100 Ioannina, Greece.
Int J Mol Sci. 2024 Sep 21;25(18):10136. doi: 10.3390/ijms251810136.
The omega-3 polyunsaturated fatty acids (PUFAs) Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) exert multiple cardioprotective effects, influencing inflammation, platelet activation, endothelial function and lipid metabolism, besides their well-established triglyceride lowering properties. It is not uncommon for omega-3 PUFAs to be prescribed for hypertriglyceridemia, alongside antiplatelet therapy in cardiovascular disease (CVD) patients. In this regard, we studied the effect of EPA and DHA, in combination with antiplatelet drugs, in platelet aggregation and P-selectin and αβ membrane expression. The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6. Both DHA and EPA displayed a dose-dependent inhibitory effect on platelet aggregation induced by AA, ADP and TRAP-6. In platelet aggregation induced by AA, DHA significantly improved acetylsalicylic acid (ASA) and triflusal's inhibitory activity, while EPA enhanced the inhibitory effect of ASA. In combination with EPA, ASA and ticagrelor expressed an increased inhibitory effect towards ADP-induced platelet activation. Both fatty acids could not improve the inhibitory effect of vorapaxar on AA- and ADP-induced platelet aggregation. In the presence of EPA, all antiplatelet drugs displayed a stronger inhibitory effect towards TRAP-6-induced platelet activation. Both omega-3 PUFAs inhibited the membrane expression of αβ, though they had no effect on P-selectin expression induced by ADP or TRAP-6. The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αβ membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αβ, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component.
ω-3 多不饱和脂肪酸（PUFAs）二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）除了具有降低甘油三酯的公认特性外，还具有多种心脏保护作用，影响炎症、血小板激活、内皮功能和脂质代谢。在心血管疾病（CVD）患者中，除了抗血小板治疗外，ω-3 PUFAs 常被开处方用于治疗高甘油三酯血症。在这方面，我们研究了 EPA 和 DHA 与抗血小板药物联合使用对血小板聚集和 P-选择素和 αβ 膜表达的影响。抗血小板药物阿司匹林和三氟柳，环氧化酶-1（COX-1）抑制剂；替格瑞洛，P2Y 受体抑制剂；vorapaxar，PAR-1 受体抑制剂，与 DHA 或 EPA 联合使用，并针对激动剂花生四烯酸（AA）、二磷酸腺苷（ADP）和 TRAP-6 诱导的体外血小板聚集进行评估。我们进一步研究了在 ADP 和 TRAP-6 刺激下，血小板中前半胱氨酸激活化合物 1（PAC-1）结合和 P-选择素膜表达。DHA 和 EPA 均对 AA、ADP 和 TRAP-6 诱导的血小板聚集呈剂量依赖性抑制作用。在 AA 诱导的血小板聚集中，DHA 显著改善了乙酰水杨酸（ASA）和三氟柳的抑制活性，而 EPA 增强了 ASA 的抑制作用。与 EPA 联合使用时，ASA 和替格瑞洛对 ADP 诱导的血小板活化表现出增强的抑制作用。两种脂肪酸都不能改善 vorapaxar 对 AA 和 ADP 诱导的血小板聚集的抑制作用。在 EPA 的存在下，所有抗血小板药物对 TRAP-6 诱导的血小板活化均表现出更强的抑制作用。两种 ω-3 PUFAs 均可抑制 αβ 的膜表达，但对 ADP 或 TRAP-6 诱导的 P-选择素表达无影响。抗血小板药物在 P-选择素和 αβ 膜表达方面表现出异质性，而两种 ω-3 PUFAs 均可抑制 αβ 的膜表达，但对 ADP 或 TRAP-6 诱导的 P-选择素表达无影响。与抗血小板药物联合使用 DHA 和 EPA 并未导致与各成分单独作用的总和相比，抑制活性增强。
