ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages

Circulation. 2018 Oct 16;138(16):1693-1705. doi: 10.1161/CIRCULATIONAHA.117.032801.

Abstract

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.

Keywords: atherosclerosis; lipoproteins, LDL; macrophages; phagocytosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Cytochrome Reductases / genetics
  • Cytochrome Reductases / metabolism
  • Diet, Western
  • Disease Models, Animal
  • Eicosapentaenoic Acid / analogs & derivatives
  • Eicosapentaenoic Acid / blood
  • Eicosapentaenoic Acid / metabolism
  • Eicosapentaenoic Acid / pharmacology*
  • Genetic Predisposition to Disease
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Necrosis
  • Oxidoreductases Acting on Sulfur Group Donors
  • Phagocytosis / drug effects*
  • Phenotype
  • Plaque, Atherosclerotic*
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Signal Transduction / drug effects

Substances

  • 18(R)-hydroxyeicosapentaenoic acid
  • CMKLR1 protein, mouse
  • Lipoproteins, LDL
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • Receptors, LDL
  • oxidized low density lipoprotein
  • Eicosapentaenoic Acid
  • Cytochrome Reductases
  • GFER protein, human
  • Oxidoreductases Acting on Sulfur Group Donors
  • 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid