Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis.

ABSTRACT: Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response.Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE-/-) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE-/- mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 ?g/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for M?1 and M?2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE-/- mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry.Liraglutide decreased atherosclerotic lesion formation in ApoE-/- mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in M?0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the M?2 surface marker mannose receptor in both M?0 and M?2 macrophages. Significant reduction in total lesion development was found with once daily 300 ?g/kg liraglutide treatment in ApoE-/- mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated M?1 markers (CCR7, IL-6 and TNF-alpha), augmented M?2 cell markers (Arg-1, IL-10 and CD163) and finally decreased M?1-like monocytes and macrophages from bone marrow-derived cells.This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards M?2 pro-resolving macrophages.

SUBMITTER: Bruen R 

PROVIDER: S-EPMC5674826 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature