title: WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice.
abstract: The role of inflammation in all stages of atherosclerosis has been actively investigated, with an emphasis on the discovery of novel and innovative drugs for treatment and prevention. The anti-inflammatory and immunomodulatory capacity of cannabinoids are well established, and these agents have a broad therapeutic potential in various inflammatory diseases, including cardiovascular diseases. The aim of this study was to investigate the effect of WIN55212-2, a synthetic cannabinoid, on atherosclerosis using the apolipoprotein E-knockout (ApoE(-/-)) mouse on a cholate-containing high-fat diet. Our results showed that WIN55212-2 reduced the size of atherosclerotic lesions in the aorta root, and did not affect serum lipid levels significantly. Furthermore, alleviation of atherosclerosis by WIN55212-2 was associated with a smaller content of macrophages in plaque lesion as well as decreasing pro-inflammatory gene expression and NF-κB activation in aortic tissues. Oxidized LDL (ox-LDL) dramatically induced NF-κB activation, and enhanced pro-inflammatory mRNA and protein expression in peritoneal macrophages isolated from ApoE(-/-) mice. It is noteworthy that all of the above-mentioned effects of ox-LDL were attenuated by WIN55212-2. Moreover, WIN55212-2 also attenuated the inflammatory response that LPS induced. AM630, a cannabinoid receptor 2 (CB₂) special antagonist completely abolished the protective effects of WIN55212-2 both in vivo and in vitro. Our data provide strong evidence that WIN55212-2 can potentially inhibit atherosclerosis in ApoE(-/-) mice. Importantly, all the beneficial effects of WIN55212-2 in our model were closely associated with the suppression of pro-inflammatory responses and were mediated by the CB₂ receptor.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhang
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xue
authors.forename: Yue Z
authors.initials: YZ
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kishimoto
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048588:Benzoxazines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D048588:Benzoxazines; D016207:Cytokines; D008077:Lipoproteins, LDL; D009025:Morpholines; D016328:NF-kappa B; D009281:Naphthalenes; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; C099252:oxidized low density lipoprotein; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone