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Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice.
- Source :
-
PloS one [PLoS One] 2018 May 29; Vol. 13 (5), pp. e0197751. Date of Electronic Publication: 2018 May 29 (Print Publication: 2018). - Publication Year :
- 2018
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Abstract
- 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 receptors in atherogenesis has been studied extensively, the significance of 2-AG for atherogenesis is less well characterized.<br />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 four weeks. Simultaneously, both groups were fed a high-cholesterol diet. The atherosclerotic plaque burden was assessed in frozen sections through the aortic sinus following oil red O staining and infiltrating macrophages were detected by immunofluorescence targeting CD68. In vitro, the effect of 2-AG on B6MCL macrophage migration was assessed by Boyden chamber experiments. Transcription of adhesion molecules and chemokine receptors in macrophages was assessed by qPCR.<br />Results: As expected, 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). ApoE-/- mice with elevated 2-AG levels displayed a significantly increased plaque burden compared to vehicle treated controls (0.44 ± 0.03 vs. 0.31 ± 0.04; n = 14; p = 0.0117). This was accompanied by a significant increase in infiltrating macrophages within the atherosclerotic vessel wall (0.33 ± 0.02 vs. 0.27 ± 0.01; n = 13-14; p = 0.0076). 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).<br />Conclusion: Taken together, elevated 2-AG levels appear to promote atherogenesis in vivo. Our data suggest that 2-AG promotes macrophage migration, possibly by the CCL5-CCR5/CCR1 axis, and thereby contributes to vascular inflammation. Thus, decreasing vascular 2-AG levels might represent a promising therapeutic strategy in patients suffering from atherosclerosis and coronary heart disease.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Antigens, CD metabolism
Antigens, Differentiation, Myelomonocytic metabolism
Atherosclerosis genetics
Atherosclerosis immunology
Benzodioxoles pharmacology
Cell Line
Cell Movement drug effects
Diet, High-Fat adverse effects
Macrophages immunology
Male
Mice
Piperidines pharmacology
Apolipoproteins E genetics
Arachidonic Acids metabolism
Atherosclerosis chemically induced
Benzodioxoles adverse effects
Endocannabinoids metabolism
Glycerides metabolism
Piperidines adverse effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 13
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 29813086
- Full Text :
- https://doi.org/10.1371/journal.pone.0197751