An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques.
An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques.
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DOI：
10.1038/ncomms12859
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发表时间：
2016-09-23
影响因子：
16.6
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Fredman, Gabrielle;Hellmann, Jason;Proto, Jonathan D.;Kuriakose, George;Colas, Romain A.;Dorweiler, Bernhard;Connolly, E. Sander;Solomon, Robert;Jones, David M.;Heyer, Eric J.;Spite, Matthew;Tabas, Ira
慢性未解决的炎症在晚期动脉粥样硬化的发展中起着因果作用，但阻止动脉粥样硬化消退的机制仍不清楚。在这里，我们使用靶向质谱法，以确定专门的前解决脂质介质（SPM）在组织学定义的稳定和脆弱的区域的人颈动脉粥样硬化斑块。SPM的水平，特别是消退素D1（RvD 1），以及SPM与促炎性白三烯B4（LTB 4）的比率，在脆弱区域中显著降低。脂肪喂养的Ldlr−/−小鼠的晚期斑块中SPM也减少。在斑块进展过程中给予这些小鼠RvD 1，可将RvD 1：LTB 4比率恢复至较不晚期病变的比率，并促进斑块稳定性，包括减少病变氧化应激和坏死，改善病变红细胞增多症和增厚纤维帽。这些发现为炎症消退缺陷导致临床危险斑块形成的概念提供了分子支持，并为SPM治疗促进斑块稳定性提供了机制依据。 动脉粥样硬化进展与血管壁的炎症过程有关。在这里，作者表明，随着动脉粥样硬化的进展，炎症的消退是由于专门的促消退脂质介质和白三烯之间的不平衡而受损。
Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB4), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr−/− mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB4 ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability. Atherosclerosis progression is linked to inflammatory processes in the blood vessel wall. Here, the authors show that, with the progression of atherosclerosis, the resolution of inflammation is impaired as the result of an imbalance between specialized pro-resolving lipid mediators and leukotrienes.
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影响因子：
64.8
作者：
Chiang, Nan;Fredman, Gabrielle;Backhed, Fredrik;Oh, Sungwhan F.;Vickery, Thad;Schmidt, Birgitta A.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
20.1
作者：
Drechsler M;de Jong R;Rossaint J;Viola JR;Leoni G;Wang JM;Grommes J;Hinkel R;Kupatt C;Weber C;Döring Y;Zarbock A;Soehnlein O
通讯作者：
Soehnlein O
影响因子：
17.1
作者：
Kamaly, Nazila;Fredman, Gabrielle;Fojas, Jhalique Jane R.;Subramanian, Manikandan;Choi, Won Ii;Zepeda, Katherine;Vilos, Cristian;Yu, Mikyung;Gadde, Suresh;Wu, Jun;Milton, Jaclyn;Leitao, Renata Carvalho;Fernandes, Livia Rosa;Hasan, Moaraj;Gao, Huayi;Vance Nguyen;Harris, Jordan;Tabas, Ira;Farokhzad, Omid C.
通讯作者：
Farokhzad, Omid C.
影响因子：
4.4
作者：
Hasturk, Hatice;Kantarci, Alpdogan;Van Dyke, Thomas E.
通讯作者：
Van Dyke, Thomas E.
影响因子：
37.8
作者：
BREZINSKI, DA;NESTO, RW;SERHAN, CN
通讯作者：
SERHAN, CN