title: Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E-/-mice.
abstract: OBJECTIVE
  Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE-/-) mice.
  
  
  METHODS
  ApoE-/-× Fpr2+/+and ApoE-/-× Fpr2-/-mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen.
  
  
  RESULTS
  ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE-/-mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE-/-mice lacking the Fpr2 receptor.
  
  
  CONCLUSIONS
  ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis.
  
  
  BACKGROUND
  This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
authors.affiliation: Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: Petri
authors.affiliation: Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrés
authors.initials: A
authors.lastname: Laguna-Fernandez
authors.affiliation: Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hildur
authors.initials: H
authors.lastname: Arnardottir
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karlinska Institutet, Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Experimental Cardiovascular Research Group, Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D005260:Female; D044045:Lipoxins / Q000494:pharmacology / Q000627:therapeutic use*; D018345:Mice, Knockout; D044042:Receptors, Formyl Peptide / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; D001241:Aspirin