Deficiency of Monoacylglycerol Lipase Enhances IgM Plasma Levels and Limits Atherogenesis in a CB2-Dependent Manner
Deficiency of Monoacylglycerol Lipase Enhances IgM Plasma Levels and Limits Atherogenesis in a CB2-Dependent Manner
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单酰甘油脂肪酶的缺乏会增强 IgM 血浆水平并以 CB2 依赖性方式限制动脉粥样硬化形成
DOI：
10.1055/s-0038-1676769
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发表时间：
2019
影响因子：
6.7
通讯作者：
Steffens S
中科院分区：
文献类型：
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作者：
Guillamat-Prats R;Rami M;Ring L;Rinne P;Lauer E;Lenglet S;Thomas A;Pagano S;Vuilleumier N;Caravatt BF;Weber C;Faussner A;Steffens S
在过去的几年中，内源性大麻素系统已成为动脉粥样硬化和代谢紊乱的病理生理激活的脂质信号系统。1内源性大麻素是内源性花生四烯酸衍生的脂质介质，通过膜脂肪酸的裂解“按需”产生，其结合大麻素受体CB 1和CB 2。基于药理学CB 1拮抗作用的临床和实验证据表明大麻素受体CB 1信号传导具有促动脉粥样硬化作用，而CB 2被认为具有动脉粥样硬化保护作用。1主要内源性配体为花生四烯酸乙醇酰胺（N-arachidonoyl ethanolamide，AEA）和花生四烯酸甘油（2-arachidonoyl glycerol，2-AG）。在动脉粥样硬化小鼠和患有冠状动脉疾病的人中，2，3患有心肌梗死4和慢性心力衰竭的患者中，5已经报道了循环内源性大麻素水平增加，并且内源性大麻素水平增加与肥胖患者的冠状动脉内皮功能障碍相关。6为了支持内源性大麻素2-AG信号在动脉粥样硬化中的因果作用，在载脂蛋白E缺乏（ApoE/ApoE）背景下遗传性缺乏2-AG代谢酶单酰基甘油脂酶（MAGL）的小鼠和9周的西式饮食喂养发展出更大但更稳定的斑块，平滑肌细胞和胶原蛋白含量增加，纤维帽更厚，而斑块脂质和巨噬细胞含量降低。7用CB 2反向激动剂处理防止了在ApoE 2/MAGL/MAGL小鼠中观察到的斑块表型，表明抑制MAGL途径通过增强的2-AG/CB 2信号传导表现出抗炎作用。CB 2主要由免疫细胞表达，并被认为具有抗炎和动脉粥样硬化保护作用。8-10此外，据报道，ApoE/ApoE/ApoE/ApoE小鼠的胆固醇代谢改变，肝脏胆固醇含量较低，这是由于胆汁分泌增强和肠道脂质吸收减少，导致西式饮食喂养后肝脏脂肪变性不太明显。11然而，在最初的研究中，遗传性MAGL缺乏对早期动脉粥样硬化斑块形成的影响没有得到解决。7在最近的一篇文章中，Jehle等人报道，在早期动脉粥样硬化形成期间，主动脉2-AG水平升高通过增强巨噬细胞迁移促进斑块形成。12只ApoEâ/â小鼠接受药理学MAGL抑制剂JZL 184治疗4周，剂量为5 mg/kg，每周腹腔注射3次，与4周的高剂量平行。
In the past few years, the endocannabinoid system has emerged as a pathophysiologically activated lipid signalling system in atherosclerosis and metabolic disorders. 1 Endocannabinoids are endogenous arachidonic acid-derived lipid mediators produced ‘on demand’by the cleavage of membrane fatty acids, which bind to cannabinoid receptors CB1 and CB2. Clinical and experimental evidence based on pharmacological CB1 antagonism suggest a pro-atherogenic role of cannabinoid receptor CB1 signalling, whereas CB2 is considered as atheroprotective. 1 The main endogenous ligands are anandamide (N-arachidonoyl ethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). Increased circulating endocannabinoid levels have been reported in atherosclerotic mice and humans with coronary artery disease, 2, 3 patients with myocardial infarction4 and chronic heart failure, 5 and increased endocannabinoid levels correlate with coronary endothelial dysfunction in obese patients. 6 In support of a causal role for endocannabinoid 2-AG signalling in atherosclerosis, mice with genetic deficiency of the 2-AG metabolizing enzyme monoacylglycerol lipase (MAGL) on apolipoprotein E deficiency (ApoEÀ/À) background and 9 weeks of Western-type diet feeding developed larger, but more stable plaques with increased smooth muscle cell and collagen content as well as thickerfibrous caps, whereas plaque lipid and macrophage content was reduced. 7 Treatment with a CB2 inverse agonist prevented the observed plaque phenotype in ApoEÀ/ÀMaglÀ/À mice, suggesting that inhibiting the MAGL pathway exhibits anti-inflammatory effects via enhanced 2-AG/CB2 signalling. 7 CB2 is predominantly expressed by immune cells and is considered to play an anti-inflammatory and atheroprotective role. 8–10 Moreover, it was reported that ApoEÀ/ÀMaglÀ/À mice have an altered cholesterol metabolism with lower hepatic cholesterol content due to enhanced biliary secretion and reduced lipid absorption in the gut, which resulted in less pronounced liver steatosis upon Westerntype diet feeding. 11 Yet, the effect of genetic MAGL deficiency on early atherosclerotic plaque formation was not addressed in the initial study. 7 In a recent article, Jehle et al reported that elevated aorta 2-AG levels during early atherogenesis promotes plaque formation by enhancing macrophage migration. 12 ApoEÀ/À mice were treated for 4 weeks with the pharmacological MAGL inhibitor JZL184 at a dose of 5 mg/kg, 3 times per week by intraperitoneal injection in parallel to 4 weeks of high-
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影响因子：
--
作者：
Vujic N;Korbelius M;Leopold C;Duta-Mare M;Rainer S;Schlager S;Goeritzer M;Kolb D;Eichmann TO;Diwoky C;Zimmer A;Zimmermann R;Lass A;Radovic B;Kratky D
通讯作者：
Kratky D
影响因子：
3.7
作者：
Jehle J;Schöne B;Bagheri S;Avraamidou E;Danisch M;Frank I;Pfeifer P;Bindila L;Lutz B;Lütjohann D;Zimmer A;Nickenig G
通讯作者：
Nickenig G
影响因子：
--
作者：
Long JZ;Nomura DK;Cravatt BF
通讯作者：
Cravatt BF
一甘油酸脂肪酶缺乏调节内源性大麻素信号传导，并改善APOE-KNOCKOUT小鼠的斑块稳定性。
影响因子：
5.3
作者：
Vujic N;Schlager S;Eichmann TO;Madreiter-Sokolowski CT;Goeritzer M;Rainer S;Schauer S;Rosenberger A;Woelfler A;Doddapattar P;Zimmermann R;Hoefler G;Lass A;Graier WF;Radovic B;Kratky D
通讯作者：
Kratky D
影响因子：
37.8
作者：
Horckmans, Michael;Bianchini, Mariaelvy;Steffens, Sabine
通讯作者：
Steffens, Sabine