Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Biology, Colby College, Waterville, ME, USA.
J Thromb Haemost. 2021 Mar;19(3):839-851. doi: 10.1111/jth.15184. Epub 2020 Dec 16.
The effects of docosahexaenoic acid (DHA) on cardiovascular disease are controversial and a mechanistic understanding of how this omega-3 polyunsaturated fatty acid (ω-3 PUFA) regulates platelet reactivity and the subsequent risk of a thrombotic event is warranted. In platelets, DHA is oxidized by 12-lipoxygenase (12-LOX) producing the oxidized lipids (oxylipins) 11-HDHA and 14-HDHA. We hypothesized that 12-LOX DHA-oxylipins may be involved in the beneficial effects observed in dietary supplemental treatment with ω-3 PUFAs or DHA itself.
To determine the effects of DHA, 11-HDHA, and 14-HDHA on platelet function and thrombus formation, and to elucidate the mechanism by which these ω-3 PUFAs regulate platelet activation.
DHA, 11-HDHA, and 14-HDHA attenuated collagen-induced human platelet aggregation, but only the oxylipins inhibited ⍺IIbβ3 activation and decreased ⍺-granule secretion. Furthermore, treatment of whole blood with DHA and its oxylipins impaired platelet adhesion and accumulation to a collagen-coated surface. Interestingly, thrombus formation was only diminished in mice treated with 11-HDHA or 14-HDHA, and mouse platelet activation was inhibited following acute treatment with these oxylipins or chronic treatment with DHA, suggesting that under physiologic conditions, the effects of DHA are mediated through its oxylipins. Finally, the protective mechanism of DHA oxylipins was shown to be mediated via activation of protein kinase A.
This study provides the first mechanistic evidence of how DHA and its 12-LOX oxylipins inhibit platelet activity and thrombus formation. These findings support the beneficial effects of DHA as therapeutic intervention in atherothrombotic diseases.
二十二碳六烯酸（DHA）对心血管疾病的影响存在争议，因此有必要深入了解这种ω-3 多不饱和脂肪酸（ω-3 PUFA）如何调节血小板反应性，以及随后发生血栓形成事件的风险。在血小板中，12-脂氧合酶（12-LOX）氧化 DHA 生成氧化脂质（oxylipins）11-HDHA 和 14-HDHA。我们假设 12-LOX DHA-氧化脂质可能参与了饮食补充 ω-3 PUFA 或 DHA 本身治疗所观察到的有益效果。
确定 DHA、11-HDHA 和 14-HDHA 对血小板功能和血栓形成的影响，并阐明这些 ω-3 PUFA 调节血小板激活的机制。
DHA、11-HDHA 和 14-HDHA 可抑制胶原诱导的人血小板聚集，但只有氧化脂质抑制 ⍺IIbβ3 激活并减少 ⍺-颗粒分泌。此外，DHA 及其氧化脂质处理全血可损害血小板黏附并聚集在胶原涂层表面。有趣的是，仅在给予 11-HDHA 或 14-HDHA 的小鼠中血栓形成减少，并且这些氧化脂质的急性处理或 DHA 的慢性处理抑制了小鼠血小板激活，这表明在生理条件下，DHA 的作用是通过其氧化脂质介导的。最后，证明了 DHA 氧化脂质的保护机制是通过蛋白激酶 A 的激活介导的。
本研究首次提供了 DHA 及其 12-LOX 氧化脂质如何抑制血小板活性和血栓形成的机制证据。这些发现支持 DHA 作为动脉血栓疾病治疗干预的有益作用。
