title: Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice.
abstract: BACKGROUND
  Omega-3 polyunsaturated fatty acids (ω3 PUFAs) suppress inflammation through activation of free fatty acid receptor 4 (FFAR4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR4 activation by ω3 PUFAs in the process of vascular inflammation and neointimal hyperplasia in mice.
  
  
  RESULTS
  We used mice with disruption of FFAR4 (Ffar4(-/-)), along with a strain that synthesizes high levels of ω3 PUFAs (fat-1) and a group of crossed mice (Ffar4(-/-)/fat-1), to elucidate the role of FFAR4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR4 in vascular-associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFAs endogenously generated in fat-1 mice (n=9), but not in compound Ffar4(-/-)/fat-1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl3. Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl3 injury in fat-1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4(-/-)/fat-1 mice.
  
  
  CONCLUSIONS
  These results indicate that ω3 PUFAs mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR4 in mice. Moreover, the ω3 PUFA-FFAR4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (X.L., L.L.B., X.C., C.D.F.).
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (X.L., L.L.B., X.C., C.D.F.).
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Ballantyne
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (X.L., L.L.B., X.C., C.D.F.).
authors.forename: Xinghui
authors.initials: X
authors.lastname: Che
authors.affiliation: Cancer Research Institute, Queen's University, Kingston, Ontario, Canada (J.D.M.).
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Mewburn
authors.affiliation: Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (J.X.K.).
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO (R.M.B., R.C.M.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Barkley
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO (R.M.B., R.C.M.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.Y.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (X.L., L.L.B., X.C., C.D.F.).
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000473:pathology / Q000503:physiopathology; D015525:Fatty Acids, Omega-3 / Q000502:physiology*; D005263:Femoral Artery / Q000473:pathology / Q000503:physiopathology; D005455:Fluorescent Antibody Technique; D006965:Hyperplasia; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000473:pathology* / Q000503:physiopathology; D014657:Vasculitis / Q000378:metabolism / Q000503:physiopathology
chemical_list: C498007:FFAR4 protein, mouse; D015525:Fatty Acids, Omega-3; D043562:Receptors, G-Protein-Coupled
keywords: adipose tissue; fatty acids; inflammation; omega‐3 fatty acid receptor; transgenic model
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