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2-arachidonoylglycerol activates pro-inflammatory pathways in murine macrophages and promotes atherogenesis in ApoE-/- mice

Session Poster Session 4

Speaker Julian Jehle

Event : ESC Congress 2018

  • Topic : basic science
  • Sub-topic : Basic Science - Vascular Diseases: Leukocytes, Inflammation, Immunity
  • Session type : Poster Session

Authors : J Jehle (Bonn,DE), B Schoene (Bonn,DE), S Bagheri (Bonn,DE), E Avraamidou (Bonn,DE), M Danisch (Bonn,DE), A Franz (Bonn,DE), P Pfeifer (Bonn,DE), L Bindila (Mainz,DE), B Lutz (Mainz,DE), D Luetjohann (Bonn,DE), A Zimmer (Bonn,DE), G Nickenig (Bonn,DE)

Authors:
J. Jehle1 , B. Schoene1 , S. Bagheri1 , E. Avraamidou1 , M. Danisch1 , A. Franz1 , P. Pfeifer1 , L. Bindila2 , B. Lutz2 , D. Luetjohann3 , A. Zimmer3 , G. Nickenig1 , 1University Hospital Bonn, Department of Cardiology - Bonn - Germany , 2Johannes Gutenberg University Mainz (JGU) - Mainz - Germany , 3University Hospital Bonn - Bonn - Germany ,

Citation:
European Heart Journal ( 2018 ) 39 ( Supplement ), 805

Background: The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation and ligand to both, pro-inflammatory cannabinoid receptor 1 (CB1) and anti-inflammatory CB2. While the role of both cannabinoid receptors in atherogenesis has been studied extensively, the influence of 2-AG on atherogenesis and the underlying molecular mechanisms are still unclear.

Methods: The impact of 2-AG on atherogenesis was studied in two treatment groups of ApoE-/- mice. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184 [5 mg/kg i.p.], which impairs 2-AG degradation and thus causes elevated 2-AG levels, the other group received vehicle for 4 weeks. Simultaneously, both groups were fed a high-cholesterol diet. The atherosclerotic plaque burden was assessed following oil red O staining and infiltrating macrophages were detected by immunofluorescence targeting CD68. In vitro, the effect of 2-AG on macrophage migration was assessed by Boyden chamber experiments. The impact of 2-AG on adhesion molecules, chemokine receptors and cholesterol metabolism was assessed by qPCR in immortalized macrophages.

Results: Application of the MAGL-inhibitor JZL184 resulted in a significant increase in 2-AG levels in vascular tissue (98.2±16.1 nmol/g vs. 27.3±4.5 nmol/g; n=14–16; p<0.001) without affecting levels of other eCBs or arachidonic acid. ApoE-/- mice with elevated 2-AG levels displayed a significantly increased plaque burden compared to vehicle treated controls (0.46±0.03 vs. 0.36±0.03; n=11–12; p=0.0391) and increased numbers of infiltrating macrophages within the atherosclerotic vessel wall (0.32±0.02 vs. 0.26±0.01; n=11; p=0.0244). While there was no alteration to the white blood counts of JZL184-treated animals, 2-AG enhanced macrophage migration in vitro by 1.8±0.2 -fold (n=4–6; p=0.0393) compared to vehicle which was completely abolished by co-administration of either CB1- or CB2-receptor-antagonists. qPCR analyses of 2-AG-stimulated macrophages showed an enhanced transcription of the chemokine CCL5 (1.59±0.23-fold; n=5–6; p=0.0589) and its corresponding receptors CCR1 (2.04±0.46-fold; n=10–11; p=0.0472) and CCR5 (2.45±0.62 –fold; n=5–6; p=0.0554). Additionally, transcription of intercellular adhesion molecule ICAM-1 was significantly increased by 2-AG (2.09±0.42 –fold; n=5–6; p=0.0447). Lastly, 2-AG increased mRNA levels of scavenging receptor CD36 which is known to promote oxLDL uptake into macrophages (8.02±1.89 –fold; n=3; p=0.0279), without affecting transcription of the cholesterol efflux transporters.

Conclusion: Taken together, elevated 2-AG levels appear to promote atherogenesis in vivo. Our data suggest that 2-AG promotes macrophage migration and might increase oxLDL accumulation in macrophages. Thus, decreasing vascular 2-AG levels might represent a novel therapeutic strategy in patients suffering from atherosclerosis and coronary heart disease.

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