Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice

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 ather...

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Veröffentlicht in:PloS one 2018-05, Vol.13 (5), p.e0197751-e0197751
Hauptverfasser: Jehle, Julian, Schöne, Benedikt, Bagheri, Sayeh, Avraamidou, Elina, Danisch, Melina, Frank, Imke, Pfeifer, Philipp, Bindila, Laura, Lutz, Beat, Lütjohann, Dieter, Zimmer, Andreas, Nickenig, Georg
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container_volume 13
creator Jehle, Julian
Schöne, Benedikt
Bagheri, Sayeh
Avraamidou, Elina
Danisch, Melina
Frank, Imke
Pfeifer, Philipp
Bindila, Laura
Lutz, Beat
Lütjohann, Dieter
Zimmer, Andreas
Nickenig, Georg
description 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. 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. 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). 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 pa
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While the role of both receptors in atherogenesis has been studied extensively, the significance of 2-AG for atherogenesis is less well characterized. 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. 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 &lt; 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). 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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0197751</identifier><identifier>PMID: 29813086</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>2-Arachidonoylglycerol ; Adhesion tests ; Animals ; Antigens, CD - metabolism ; Antigens, Differentiation, Myelomonocytic - metabolism ; Aorta ; Apolipoprotein E ; Apolipoproteins E - genetics ; Arachidonic Acids - metabolism ; Arteriosclerosis ; Atherogenesis ; Atherosclerosis ; Atherosclerosis - chemically induced ; Atherosclerosis - genetics ; Atherosclerosis - immunology ; Benzodioxoles - adverse effects ; Benzodioxoles - pharmacology ; Biology and Life Sciences ; Boyden chamber ; Cannabinoid CB2 receptors ; Cardiology ; Cardiovascular disease ; Cardiovascular diseases ; CC chemokine receptors ; CCR1 protein ; CCR5 protein ; Cell Line ; Cell Movement - drug effects ; Chemokine receptors ; Chemokines ; Cholesterol ; Coronary artery disease ; Data processing ; Diet, High-Fat - adverse effects ; Endocannabinoids - metabolism ; Glycerides - metabolism ; Heart ; Heart diseases ; High cholesterol diet ; Hospitals ; Immunofluorescence ; Inflammation ; Inhibitors ; Internal medicine ; Leukocyte migration ; Ligands ; Lipase ; Macrophages ; Macrophages - immunology ; Male ; Medicine ; Medicine and Health Sciences ; Metabolism ; Mice ; Molecular chains ; Oils &amp; fats ; Physiology ; Piperidines - adverse effects ; Piperidines - pharmacology ; Receptors ; Research and Analysis Methods ; Transcription ; Vascular tissue</subject><ispartof>PloS one, 2018-05, Vol.13 (5), p.e0197751-e0197751</ispartof><rights>2018 Jehle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Jehle et al 2018 Jehle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-d1f1f6707252cf868e74a355ac5993ce5b96cdc04985bf29cf1c135735734dc3</citedby><cites>FETCH-LOGICAL-c526t-d1f1f6707252cf868e74a355ac5993ce5b96cdc04985bf29cf1c135735734dc3</cites><orcidid>0000-0002-2719-9692</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973571/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973571/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29813086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bader, Michael</contributor><creatorcontrib>Jehle, Julian</creatorcontrib><creatorcontrib>Schöne, Benedikt</creatorcontrib><creatorcontrib>Bagheri, Sayeh</creatorcontrib><creatorcontrib>Avraamidou, Elina</creatorcontrib><creatorcontrib>Danisch, Melina</creatorcontrib><creatorcontrib>Frank, Imke</creatorcontrib><creatorcontrib>Pfeifer, Philipp</creatorcontrib><creatorcontrib>Bindila, Laura</creatorcontrib><creatorcontrib>Lutz, Beat</creatorcontrib><creatorcontrib>Lütjohann, Dieter</creatorcontrib><creatorcontrib>Zimmer, Andreas</creatorcontrib><creatorcontrib>Nickenig, Georg</creatorcontrib><title>Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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. 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. 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 &lt; 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). 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.</description><subject>2-Arachidonoylglycerol</subject><subject>Adhesion tests</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>Antigens, Differentiation, Myelomonocytic - metabolism</subject><subject>Aorta</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins E - genetics</subject><subject>Arachidonic Acids - metabolism</subject><subject>Arteriosclerosis</subject><subject>Atherogenesis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - chemically induced</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - immunology</subject><subject>Benzodioxoles - adverse effects</subject><subject>Benzodioxoles - pharmacology</subject><subject>Biology and Life Sciences</subject><subject>Boyden chamber</subject><subject>Cannabinoid CB2 receptors</subject><subject>Cardiology</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>CC chemokine receptors</subject><subject>CCR1 protein</subject><subject>CCR5 protein</subject><subject>Cell Line</subject><subject>Cell Movement - drug effects</subject><subject>Chemokine receptors</subject><subject>Chemokines</subject><subject>Cholesterol</subject><subject>Coronary artery disease</subject><subject>Data processing</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Endocannabinoids - metabolism</subject><subject>Glycerides - metabolism</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>High cholesterol diet</subject><subject>Hospitals</subject><subject>Immunofluorescence</subject><subject>Inflammation</subject><subject>Inhibitors</subject><subject>Internal medicine</subject><subject>Leukocyte migration</subject><subject>Ligands</subject><subject>Lipase</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Molecular chains</subject><subject>Oils &amp; fats</subject><subject>Physiology</subject><subject>Piperidines - adverse effects</subject><subject>Piperidines - pharmacology</subject><subject>Receptors</subject><subject>Research and Analysis Methods</subject><subject>Transcription</subject><subject>Vascular tissue</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1r3DAUNKEhSdP-g9IaeunFG31YknUphLBtA4Fcchfy89OuF9lyJW9g_33trBOSEhA8PWlmNE9Mln2hZEW5ole7sI-99ash9LgiVCsl6El2QTVnhWSEf3i1P88-prQjRPBKyrPsnOmKclLJi-x-7fHRjtjkU0Wf8uByVthoYds2oQ8Hv_EHwBh8PsTQhRFzO26nfoM9pjblbZ9fD2FdXBV51wJ-yk6d9Qk_L_Uye_i1frj5U9zd_769ub4rQDA5Fg111ElFFBMMXCUrVKXlQlgQWnNAUWsJDZBSV6J2TIOjQLlQ8yob4JfZt6Ps4EMyy1ckw0gpRaUpVRPi9ohogt2ZIbadjQcTbGueDkLcGBvHFjwaXToHAM7WTpdKKVtTIQgntqS1FjWbtH4ur-3rDhvAfozWvxF9e9O3W7MJj0bo2TGdBH4sAjH83WMaTdcmQO9tj2H_5FsxWVXlDP3-H_T96cojCmJIKaJ7MUOJmePxzDJzPMwSj4n29fUgL6TnPPB_Wcq4iA</recordid><startdate>20180529</startdate><enddate>20180529</enddate><creator>Jehle, Julian</creator><creator>Schöne, Benedikt</creator><creator>Bagheri, Sayeh</creator><creator>Avraamidou, Elina</creator><creator>Danisch, Melina</creator><creator>Frank, Imke</creator><creator>Pfeifer, Philipp</creator><creator>Bindila, Laura</creator><creator>Lutz, Beat</creator><creator>Lütjohann, Dieter</creator><creator>Zimmer, Andreas</creator><creator>Nickenig, Georg</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2719-9692</orcidid></search><sort><creationdate>20180529</creationdate><title>Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice</title><author>Jehle, Julian ; Schöne, Benedikt ; Bagheri, Sayeh ; Avraamidou, Elina ; Danisch, Melina ; Frank, Imke ; Pfeifer, Philipp ; Bindila, Laura ; Lutz, Beat ; Lütjohann, Dieter ; Zimmer, Andreas ; Nickenig, Georg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-d1f1f6707252cf868e74a355ac5993ce5b96cdc04985bf29cf1c135735734dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>2-Arachidonoylglycerol</topic><topic>Adhesion tests</topic><topic>Animals</topic><topic>Antigens, CD - metabolism</topic><topic>Antigens, Differentiation, Myelomonocytic - metabolism</topic><topic>Aorta</topic><topic>Apolipoprotein E</topic><topic>Apolipoproteins E - genetics</topic><topic>Arachidonic Acids - metabolism</topic><topic>Arteriosclerosis</topic><topic>Atherogenesis</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - chemically induced</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - immunology</topic><topic>Benzodioxoles - adverse effects</topic><topic>Benzodioxoles - pharmacology</topic><topic>Biology and Life Sciences</topic><topic>Boyden chamber</topic><topic>Cannabinoid CB2 receptors</topic><topic>Cardiology</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>CC chemokine receptors</topic><topic>CCR1 protein</topic><topic>CCR5 protein</topic><topic>Cell Line</topic><topic>Cell Movement - drug effects</topic><topic>Chemokine receptors</topic><topic>Chemokines</topic><topic>Cholesterol</topic><topic>Coronary artery disease</topic><topic>Data processing</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Endocannabinoids - metabolism</topic><topic>Glycerides - metabolism</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>High cholesterol diet</topic><topic>Hospitals</topic><topic>Immunofluorescence</topic><topic>Inflammation</topic><topic>Inhibitors</topic><topic>Internal medicine</topic><topic>Leukocyte migration</topic><topic>Ligands</topic><topic>Lipase</topic><topic>Macrophages</topic><topic>Macrophages - immunology</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Molecular chains</topic><topic>Oils &amp; 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Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jehle, Julian</au><au>Schöne, Benedikt</au><au>Bagheri, Sayeh</au><au>Avraamidou, Elina</au><au>Danisch, Melina</au><au>Frank, Imke</au><au>Pfeifer, Philipp</au><au>Bindila, Laura</au><au>Lutz, Beat</au><au>Lütjohann, Dieter</au><au>Zimmer, Andreas</au><au>Nickenig, Georg</au><au>Bader, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-05-29</date><risdate>2018</risdate><volume>13</volume><issue>5</issue><spage>e0197751</spage><epage>e0197751</epage><pages>e0197751-e0197751</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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. 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. 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 &lt; 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). 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29813086</pmid><doi>10.1371/journal.pone.0197751</doi><orcidid>https://orcid.org/0000-0002-2719-9692</orcidid><oa>free_for_read</oa></addata></record>
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subjects 2-Arachidonoylglycerol
Adhesion tests
Animals
Antigens, CD - metabolism
Antigens, Differentiation, Myelomonocytic - metabolism
Aorta
Apolipoprotein E
Apolipoproteins E - genetics
Arachidonic Acids - metabolism
Arteriosclerosis
Atherogenesis
Atherosclerosis
Atherosclerosis - chemically induced
Atherosclerosis - genetics
Atherosclerosis - immunology
Benzodioxoles - adverse effects
Benzodioxoles - pharmacology
Biology and Life Sciences
Boyden chamber
Cannabinoid CB2 receptors
Cardiology
Cardiovascular disease
Cardiovascular diseases
CC chemokine receptors
CCR1 protein
CCR5 protein
Cell Line
Cell Movement - drug effects
Chemokine receptors
Chemokines
Cholesterol
Coronary artery disease
Data processing
Diet, High-Fat - adverse effects
Endocannabinoids - metabolism
Glycerides - metabolism
Heart
Heart diseases
High cholesterol diet
Hospitals
Immunofluorescence
Inflammation
Inhibitors
Internal medicine
Leukocyte migration
Ligands
Lipase
Macrophages
Macrophages - immunology
Male
Medicine
Medicine and Health Sciences
Metabolism
Mice
Molecular chains
Oils & fats
Physiology
Piperidines - adverse effects
Piperidines - pharmacology
Receptors
Research and Analysis Methods
Transcription
Vascular tissue
title Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice
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