title: Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin.
abstract: Besides LDL-cholesterol, local vascular inflammation plays a key role in atherogenesis. Efficient therapies to treat the inflammatory component of the disease have not been established. The discovery of specialized inflammation-resolving mediators, such as resolvins may provide new opportunities for treatment. This study examines whether the ω-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1), can reduce atherosclerosis, when administered alone or in combination with a cholesterol-lowering statin.
  
  
  
  ApoE*3Leiden mice were fed a hypercholesterolemic diet for 9 weeks and subsequently treated with RvE1-low (1 mg/kg/day), RvE1-high (5 mg/kg/day), atorvastatin (1.5 mg/kg/day) or the combination of atorvastatin and RvE1-low for the following 16 weeks.
  
  
  
  RvE1-low and RvE1-high reduced atherosclerotic lesion size to the same extent (-35%; p < 0.05), attenuated the formation of severe lesions, also seen as a proportional increase in the presence of mild lesions, but did not alter plasma cholesterol levels. Cholesterol-lowering atorvastatin reduced atherosclerosis (-27%, p < 0.05), and the combination of RvE1 and atorvastatin further attenuated lesion size (-51%, p < 0.01) and increased the content of mild lesions. RvE1 did not affect plasma SAA, E-selectin, VCAM-1 or MCP-1 but did reduce plasma EPHX4 and down-regulated the local expression of pro-atherogenic genes in the aortae, (e.g. Cd74, Cd44, Ccl2, Ccr5 and Adam17) and significantly inactivated IFN-γ (p < 0.001) and TNF-α (p < 0.001) signalling pathways.
  
  
  
  RvE1 attenuates atherogenesis both alone and on top of a statin. The local effects of RvE1 are demonstrated by the modulated aortic expression of genes involved in inflammatory and immune responses, without altering plasma cholesterol or circulating SAA.
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK, Leiden, The Netherlands. Electronic address: kanita.salic@tno.nl.
authors.forename: Kanita
authors.initials: K
authors.lastname: Salic
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK, Leiden, The Netherlands.
authors.forename: Martine C
authors.initials: MC
authors.lastname: Morrison
authors.affiliation: Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), Utrechtseweg 48, 3704 HE, Zeist, The Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK, Leiden, The Netherlands.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Wielinga
authors.affiliation: Resolvyx Pharmaceuticals, Inc., 222 Third Street, Cambridge, MA, 02142, United States.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK, Leiden, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.affiliation: Resolvyx Pharmaceuticals, Inc., 222 Third Street, Cambridge, MA, 02142, United States. Electronic address: pgjorstrup@anidapharma.com.
authors.forename: Per
authors.initials: P
authors.lastname: Gjorstrup
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK, Leiden, The Netherlands.
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D050197:Atherosclerosis / Q000097:blood; D000069059:Atorvastatin / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D019040:E-Selectin / Q000097:blood; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008055:Lipids / Q000097:blood*; D051379:Mice; D000074085:Mice, Knockout, ApoE; D020411:Oligonucleotide Array Sequence Analysis; D000685:Serum Amyloid A Protein / Q000378:metabolism; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D008078:Cholesterol, LDL; D019040:E-Selectin; D015525:Fatty Acids, Omega-3; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D000685:Serum Amyloid A Protein; D019010:Vascular Cell Adhesion Molecule-1; D002784:Cholesterol; D000069059:Atorvastatin; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
keywords: Atherosclerosis; Inflammation; Resolution; Resolvin E1; Statin