title: Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet.
abstract: OBJECTIVE
  To investigate therapeutic effects of annexin A1 (anxA1) on atherogenesis in LDLR-/- mice.
  
  
  METHODS
  Human recombinant annexin A1 (hr-anxA1) was produced by a prokaryotic expression system, purified and analysed on phosphatidylserine (PS) binding and formyl peptide receptor (FPR) activation. Biodistribution of 99mTechnetium-hr-anxA1 was determined in C57Bl/6J mice. 12 Weeks old LDLR-/- mice were fed a Western Type Diet (WTD) during 6 weeks (Group I) or 12 weeks (Group P). Mice received hr-anxA1 (1 mg/kg) or vehicle by intraperitoneal injection 3 times per week for a period of 6 weeks starting at start of WTD (Group I) or 6 weeks after start of WTD (Group P). Total aortic plaque burden and phenotype were analyzed using immunohistochemistry.
  
  
  RESULTS
  Hr-anxA1 bound PS in Ca2+-dependent manner and activated FPR2/ALX. It inhibited rolling and adherence of neutrophils but not monocytes on activated endothelial cells. Half lives of circulating 99mTc-hr-anxA1 were <10 minutes and approximately 6 hours for intravenously (IV) and intraperitoneally (IP) administered hr-anxA1, respectively. Pharmacological treatment with hr-anxA1 had no significant effect on initiation of plaque formation (-33%; P = 0.21)(Group I) but significantly attenuated progression of existing plaques of aortic arch and subclavian artery (plaque size -50%, P = 0.005; necrotic core size -76% P = 0.015, hr-anxA1 vs vehicle) (Group P).
  
  
  CONCLUSIONS
  Hr-anxA1 may offer pharmacological means to treat chronic atherogenesis by reducing FPR-2 dependent neutrophil rolling and adhesion to activated endothelial cells and by reducing total plaque inflammation.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Dennis H M
authors.initials: DH
authors.lastname: Kusters
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Chatrou
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; VitaK BV, Maastricht University, Maastricht, the Netherlands.
authors.forename: Brecht A G
authors.initials: BA
authors.lastname: Willems
authors.affiliation: Department of Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: De Saint-Hubert
authors.affiliation: Department of Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bauwens
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Emiel
authors.initials: E
authors.lastname: van der Vorst
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bena
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
authors.forename: Chris P M
authors.initials: CP
authors.lastname: Reutelingsperger
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000008:administration & dosage / Q000494:pharmacology*; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D066273:Diet, Western / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004333:Drug Administration Routes; D006801:Humans; D016130:Immunophenotyping; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D011994:Recombinant Proteins
chemical_list: D017305:Annexin A1; D011973:Receptors, LDL; D011994:Recombinant Proteins