期刊
CIRCULATION
卷 138, 期 16, 页码 1693-1705出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.117.032801
关键词
atherosclerosis; lipoproteins; LDL; macrophages; phagocytosis
资金
- Swedish Research Council [2014-2312]
- Swedish Heart and Lung Foundation [20150600, 20150683]
- Marianne and Marcus Wallenberg Foundation [MMW 2015.0104]
- King Gustaf V and Queen Victoria Freemason Foundation
- Stockholm County Council [20170365]
- Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC Linnaeus Program) [349-2007-8703]
- Nanna Svartz Fond
- Fredrik och Ingrid Thurings Stiftelse
- Stiftelsen for Gamla Tjanarinnor
- Foundation for Geriatric Diseases at Karolinska Institutet
- Sir Henry Dale Fellowship - Wellcome Trust [107613/Z/15/Z]
- Sir Henry Dale Fellowship - Royal Society [107613/Z/15/Z]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [677542]
- Barts Charity [MGU0343]
Background: In addition to enhanced proinflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Proresolving lipid mediators formed through the 12/15 lipoxygenase pathways exert protective effects against murine atherosclerosis. n-3 Polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), serve as the substrate for the formation of lipid mediators, which transduce potent anti-inflammatory and proresolving actions through their cognate G-protein-coupled receptors. The aim of this study was to identify signaling pathways associated with EPA supplementation and lipid mediator formation that mediate atherosclerotic disease progression. Methods: Lipidomic plasma analysis were performed after EPA supplementation in Apoe(-/-) mice. Erv1/Chemr23(-/-)xApoe(-/-) mice were generated for the evaluation of atherosclerosis, phagocytosis, and oxidized low-density lipoprotein uptake. Histological and mRNA analyses were done on human atherosclerotic lesions. Results: Here, we show that EPA supplementation significantly attenuated atherosclerotic lesion growth induced by Western diet in Apoe(-/-) mice and was associated with local cardiovascular n-3 enrichment and altered lipoprotein metabolism. Our systematic plasma lipidomic analysis identified the resolvin E1 precursor 18-monohydroxy EPA as a central molecule formed during EPA supplementation. Targeted deletion of the resolvin E1 receptor Erv1/Chemr23 in 2 independent hyperlipidemic murine models was associated with proatherogenic signaling in macrophages, increased oxidized low-density lipoprotein uptake, reduced phagocytosis, and increased atherosclerotic plaque size and necrotic core formation. We also demonstrate that in macrophages the resolvin E1-mediated effects in oxidized low-density lipoprotein uptake and phagocytosis were dependent on Erv1/Chemr23. When analyzing human atherosclerotic specimens, we identified ERV1/ChemR23 expression in a population of macrophages located in the proximity of the necrotic core and demonstrated augmented ERV1/ChemR23 mRNA levels in plaques derived from statin users. Conclusions: This study identifies 18-monohydroxy EPA as a major plasma marker after EPA supplementation and demonstrates that the ERV1/ChemR23 receptor for its downstream mediator resolvin E1 transduces protective effects in atherosclerosis. ERV1/ChemR23 signaling may represent a previously unrecognized therapeutic pathway to reduce atherosclerotic cardiovascular disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据