Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet

PLoS One. 2015 Jun 19;10(6):e0130484. doi: 10.1371/journal.pone.0130484. eCollection 2015.

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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1 / administration & dosage
  • Annexin A1 / pharmacology*
  • Blood Cells / metabolism
  • Bone Marrow Cells / metabolism
  • Diet, Western / adverse effects
  • Disease Models, Animal
  • Disease Progression
  • Drug Administration Routes
  • Humans
  • Immunophenotyping
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Plaque, Atherosclerotic / drug therapy
  • Plaque, Atherosclerotic / etiology
  • Plaque, Atherosclerotic / genetics*
  • Plaque, Atherosclerotic / pathology*
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Recombinant Proteins*

Substances

  • Annexin A1
  • Receptors, LDL
  • Recombinant Proteins

Grants and funding

Part of this work was financially supported by the European Union through the Interreg IV program of Grensregio Vlaanderen-Nederland to Euregional PACT II (VLA-NED 1.20). The remaining of the funding is provided by Maastricht University directly to Prof. Chris Reutelingsperger. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.