Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice.
Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice.
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DOI：
10.1161/circresaha.116.309492
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发表时间：
2016-08
影响因子：
20.1
通讯作者：
Joana R. Viola;Patricia Lemnitzer;Y. Jansen;G. Csaba;Carla Winter;Carlos Neideck;C. Silvestre-Roig;G. Dittmar;Y. Döring;Maik Drechsler;C. Weber;R. Zimmer;N. Cenac;O. Soehnlein
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文献类型：
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作者：
Joana R. Viola;Patricia Lemnitzer;Y. Jansen;G. Csaba;Carla Winter;Carlos Neideck;C. Silvestre-Roig;G. Dittmar;Y. Döring;Maik Drechsler;C. Weber;R. Zimmer;N. Cenac;O. Soehnlein
理论基础：动脉粥样硬化是炎症未消退的结果，目前缺乏对其消退机制的全面概述。然而，在急性炎症中，已知通过从炎症到溶解脂质介质的转换来协调解决。因此，我们假设病变脂质介质失衡有利于动脉粥样硬化的进展。目的了解动脉粥样硬化进展过程中脂质介质的平衡，并建立基于溶解脂质介质输送的介入策略。方法和结果：Apoe-/-小鼠高脂饮食4周、8周或4个月的主动脉脂质介质分析显示，在晚期动脉粥样硬化期间，炎症性脂质介质白三烯B4和前列腺素E2增加，溶解性脂质介质Resolvin D2 （RvD2）和marsin 1 （MaR1）减少。在功能上，主动脉白三烯B4和前列腺素E2水平与斑块不稳定的特征相关，而RvD2和MaR1水平与斑块稳定的迹象相关。在治疗方面，重复的RvD2和MaR1递送可以阻止动脉粥样硬化的进展，其特征是停止坏死核心的扩张和巨噬细胞的积累，同时增加纤维帽厚度和平滑肌细胞数量。从机制上讲，RvD2和MaR1诱导巨噬细胞向修复表型转变，从而继发刺激平滑肌细胞的胶原合成。结论：我们提供了动脉粥样硬化过程中炎症和溶解性脂质介质不平衡的证据。RvD2和MaR1的递送成功地阻止了动脉粥样硬化的进展，这表明溶解脂质介质可能代表了一种解决动脉炎症的创新策略。
RATIONALE Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression. OBJECTIVE To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators. METHODS AND RESULTS Aortic lipid mediator profiling of aortas from Apoe-/- mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells. CONCLUSIONS We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.