Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice.
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-A...
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doaj-94ffcccfabf94777ab155030a41b95b22020-11-25T02:05:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019775110.1371/journal.pone.0197751Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice.Julian JehleBenedikt SchöneSayeh BagheriElina AvraamidouMelina DanischImke FrankPhilipp PfeiferLaura BindilaBeat LutzDieter LütjohannAndreas ZimmerGeorg NickenigBACKGROUND: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. 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. 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). 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.http://europepmc.org/articles/PMC5973571?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julian Jehle Benedikt Schöne Sayeh Bagheri Elina Avraamidou Melina Danisch Imke Frank Philipp Pfeifer Laura Bindila Beat Lutz Dieter Lütjohann Andreas Zimmer Georg Nickenig |
spellingShingle |
Julian Jehle Benedikt Schöne Sayeh Bagheri Elina Avraamidou Melina Danisch Imke Frank Philipp Pfeifer Laura Bindila Beat Lutz Dieter Lütjohann Andreas Zimmer Georg Nickenig Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. PLoS ONE |
author_facet |
Julian Jehle Benedikt Schöne Sayeh Bagheri Elina Avraamidou Melina Danisch Imke Frank Philipp Pfeifer Laura Bindila Beat Lutz Dieter Lütjohann Andreas Zimmer Georg Nickenig |
author_sort |
Julian Jehle |
title |
Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. |
title_short |
Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. |
title_full |
Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. |
title_fullStr |
Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. |
title_full_unstemmed |
Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. |
title_sort |
elevated levels of 2-arachidonoylglycerol promote atherogenesis in apoe-/- mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
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. 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. 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). 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. |
url |
http://europepmc.org/articles/PMC5973571?pdf=render |
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