Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or G_q signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34^Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ–S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1–G_q–Ca²⁺–eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.

Omega-3 多不饱和脂肪酸 (ω-3 PUFA) 与潜在的心血管益处相关，部分归因于其生物活性代谢物。然而，造成这些优势的潜在机制尚未完全了解。我们之前报道过二十碳五烯酸（EPA）衍生的细胞色素P450途径的代谢物介导了ω-3 PUFA的动脉粥样硬化保护作用。在这里，我们证明内皮细胞 (EC) 中的 17,18-环氧二十碳四烯酸 (17,18-EEQ) 及其受体 1-磷酸鞘氨醇受体 1 (S1PR1) 可以抑制振荡剪切应力或肿瘤坏死因子 -培养的人 EC 中 α 诱导的内皮激活。值得注意的是，在内皮 S1PR1 缺陷的雄性小鼠中，17,18-EEQ 和纯化 EPA 的动脉粥样硬化保护作用被规避。从机制上讲，17,18-EEQ 的抗炎作用依赖于钙释放介导的内皮一氧化氮合酶 (eNOS) 激活，而这种激活会在抑制 S1PR1 或 G _q信号传导后被消除。此外，17,18-EEQ 通过与 Lys34 ^{Nter 的}极性相互作用来变构调节 S1PR1 的构象。最后，我们证明 Vascepa 是一种含有高度纯化且稳定的 EPA 乙酯的处方药，通过 17,18-EEQ-S1PR1 通路在雄性和雌性小鼠中发挥心血管保护作用。总的来说，我们的研究结果表明，17,18-EEQ 的抗炎作用涉及 EC 中 S1PR1–G _q –Ca ²⁺ –eNOS 轴的激活，为动脉粥样硬化提供了潜在的治疗靶点。