| First Author | Jehle J | Year | 2018 |
| Journal | PLoS One | Volume | 13 |
| Issue | 5 | Pages | e0197751 |
| PubMed ID | 29813086 | Mgi Jnum | J:263298 |
| Mgi Id | MGI:6160366 | Doi | 10.1371/journal.pone.0197751 |
| Citation | Jehle J, et al. (2018) Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. PLoS One 13(5):e0197751 |
| abstractText | 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. |
