摘要 415：Resolvin D1 通过抑制钙激活激酶途径限制 5-脂氧合酶核定位和白三烯 B4 合成,Arteriosclerosis, Thrombosis, and Vascular Biology

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摘要 415：Resolvin D1 通过抑制钙激活激酶途径限制 5-脂氧合酶核定位和白三烯 B4 合成
Arteriosclerosis, Thrombosis, and Vascular Biology ( IF 7.4 ) Pub Date : 2021-07-03 , DOI: 10.1161/atvb.35.suppl_1.415
Gabrielle Fredman ₁

Affiliation

介绍：促炎介质和促消退介质之间的不平衡可能导致慢性炎症疾病，例如动脉粥样硬化。假设：白细胞中花生四烯酸 (AA) 衍生介质的平衡被认为是通过 5-脂氧合酶 (5-LOX) 的细胞内定位实现的：核 5-LOX 有利于促炎性白三烯 B 的生物合成4（LTB4），而理论上，细胞质 5-LOX 可能有利于促分解脂氧素 A 的生物合成4(LXA4）。这种平衡有利于 LXA4resolvin D1 (RvD1) 是一种源自二十二碳六烯酸 (DHA) 的专门促分解介质 (SPM)，但其机制尚不清楚。因此我们假设 RvD1 调节巨噬细胞中的 5-LOX 定位。方法/结果：在这里，我们报告了一种新途径，RvD1 通过该途径促进 5-LOX 的核排除，从而抑制 LTB4并增强LXA4在巨噬细胞中。RvD1 通过激活其受体 FPR2/ALX，抑制胞质钙并降低钙敏感激酶 CaMKII 的激活。CaMKII 抑制可抑制 P38 和 MAPKAPK2 激酶的激活，从而减少 5-LOX 的 Ser271 磷酸化并将 5-LOX 从细胞核转移到细胞质。因此，RvD1 能够降低核 5-LOX 和 LTB4:LXA4比率体外和体内缺乏 CaMKII 或表达 S271A-5-LOX 的巨噬细胞模仿。重要的是，据报道，5-LOX 的核定位在不稳定的晚期人类动脉粥样硬化病变中，因此逆转这一过程的策略令人感兴趣。在这方面，RvD1治疗低密度脂蛋白 -/-小鼠减少巨噬细胞 5-LOX 定位并稳定晚期斑块。结论：了解这种机制可能为促进动脉粥样硬化等慢性炎症疾病的炎症消退提供新策略。

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Abstract 415: Resolvin D1 Limits 5-lipoxygenase Nuclear Localization and Leukotriene B4 Synthesis by Inhibiting a Calcium-activated Kinase Pathway

Introduction: Imbalances between pro-inflammatory and pro-resolving mediators can lead to chronic inflammatory diseases, such as atherosclerosis. Hypothesis: The balance of arachidonic acid (AA)-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of pro-inflammatory leukotriene B 4 (LTB 4 ), while, in theory, cytoplasmic 5-LOX could favor the biosynthesis of pro-resolving lipoxin A 4 (LXA 4 ). This balance is shifted in favor of LXA 4 by resolvin D1 (RvD1), a specialized pro-resolving mediator (SPM) derived from docosahexaenoic acid (DHA), but the mechanism is not known. Hence we hypothesized that RvD1 regulates 5-LOX localization in macrophages. Methods/Results: Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB 4 and enhances LXA 4 in macrophages. RvD1, by activating its receptor FPR2/ALX, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase CaMKII. CaMKII inhibition suppresses activation P38 and MAPKAPK2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1’s ability to decrease nuclear 5-LOX and the LTB 4 :LXA 4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. Importantly, nuclear localization of 5-LOX has been reported in unstable advanced human atherosclerotic lesions, hence strategies to reverse this process are of interest. In this regard, RvD1 treatment of Ldlr -/- mice reduced macrophage 5-LOX localization and stabilized advanced plaques. Conclusions: Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases, like atherosclerosis.

更新日期：2021-07-03

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