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- Title
Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR<sup>-/-</sup> Mice on Western Type Diet.
- Authors
Kusters, Dennis H. M.; Chatrou, Martijn L.; Willems, Brecht A. G.; De Saint-Hubert, Marijke; Bauwens, Matthias; van der Vorst, Emiel; Bena, Stefania; Biessen, Erik A. L.; Perretti, Mauro; Schurgers, Leon J.; Reutelingsperger, Chris P. M.
- 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.
- Subjects
ANNEXINS; ATHEROSCLEROTIC plaque; RECOMBINANT proteins; GENE expression; PHOSPHATIDYLSERINES; LABORATORY mice
- Publication
PLoS ONE, 2015, Vol 10, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0130484