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

D.H. Kusters, M.L. Chatrou, B.A. Willems, M. De Saint-Hubert, Matthias Bauwens, E. van der Vorst, S. Bena, E. A. Biessen, M. Perretti, L.J. Schurgers, C.P. Reutelingsperger

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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.
Original languageEnglish
Article numbere0130484
Number of pages15
JournalPLOS ONE
Volume10
Issue number6
DOIs
Publication statusPublished - 19 Jun 2015

Keywords

  • SURFACE-EXPRESSED PHOSPHATIDYLSERINE
  • FORMYL PEPTIDE RECEPTOR
  • IN-VIVO
  • NEUTROPHILS
  • INFLAMMATION
  • MECHANISMS
  • CLEAVAGE
  • A5
  • PHAGOCYTOSIS
  • ENDOTHELIUM

Cite this

Kusters, D. H., Chatrou, M. L., Willems, B. A., De Saint-Hubert, M., Bauwens, M., van der Vorst, E., Bena, S., Biessen, E. A., Perretti, M., Schurgers, L. J., & Reutelingsperger, C. P. (2015). Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet. PLOS ONE, 10(6), [e0130484]. https://doi.org/10.1371/journal.pone.0130484