Abstract
ObjectiveTo investigate therapeutic effects of annexin A1 (anxA1) on atherogenesis in LDLR-/- mice.MethodsHuman 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.ResultsHr-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).ConclusionHr-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.
Highlights
Atherosclerosis is a systemic chronic inflammatory disease affecting the vascular wall of arteries and is the major cause of morbidity and mortality in both developed and developing countries
Pharmacological treatment with hr-annexin A1 (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 (Group P)
In order to verify that our procedure yielded full-length recombinant product, purified hr-anxA1 was subjected to structural analyses including MALDI TOF/TOF, silver stained SDS-PAGE and Western blotting (S1 Fig) and tryptic digestion
Summary
Atherosclerosis is a systemic chronic inflammatory disease affecting the vascular wall of arteries and is the major cause of morbidity and mortality in both developed and developing countries. The disease is characterized by confined manifestations of atherosclerotic lesions in the arterial vessel wall that may develop into unstable plaques causing adverse outcomes over time [1,2,3]. Unstable plaques are characterized by abundant presence of inflammatory cells, a large necrotic core and a thin fibrous cap [4]. Reducing recruitment of neutrophils to the inflamed arterial vessel wall by neutrophil-specific antibodies and genedeletions of chemokines and their receptors, suppresses arterial lesion development in mouse models of atherosclerosis [8,9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
