ERV1/ChemR23 Signaling Protects from Atherosclerosis by Modifying oxLDL Uptake and Phagocytosis in Macrophages
Background—In addition to enhanced pro-inflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Pro-resolving 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 pro-resolving 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 after EPA supplementation in Apoe-/- mice. Generation of Erv1/Chemr23-/-xApoe-/- mice for the evaluation of atherosclerosis, phagocytosis, and oxidized low density lipoprotein (oxLDL) uptake. Histological and mRNA analysis 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 (RvE1)-precursor, 18-monohydroxy eicosapentaenoic acid (18-HEPE), as a central molecule formed during EPA supplementation. Targeted deletion of the RvE1 receptor, Erv1/Chemr23, in two independent hyperlipidemic murine models was associated with pro-atherogenic signaling in macrophages, increased oxLDL uptake, reduced phagocytosis, and increased atherosclerotic plaque size and necrotic core formation. We also demonstrate that in macrophages, the RvE1-mediated effects in oxLDL uptake and phagocytosis are 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 its augmented mRNA expression in plaques derived from statin users.
Conclusions—This study identifies 18-HEPE as a major plasma marker following EPA supplementation and demonstrates that the ERV1/ChemR23 receptor for its downstream mediator RvE1 transduces protective effects in atherosclerosis. In conclusion, ERV1/ChemR23 signaling may represent a previously unrecognized therapeutic pathway to reduce atherosclerotic cardiovascular disease.
- Received November 16, 2017.
- Revision received March 23, 2018.
- Accepted April 20, 2018.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.