Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice.
Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice.
复制标题
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。
DOI：
10.1016/j.atherosclerosis.2015.10.109
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发表时间：
2016-01
期刊：
影响因子：
5.3
通讯作者：
Kratky D
中科院分区：
文献类型：
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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
单甘油酯脂肪酶（MGL）通过将单甘油酯（MG）降解为甘油和脂肪酸来催化脂肪分解的最后一步。MGL还能水解并使2-花生四烯醇甘油（2-AG）失活，2-AG是哺乳动物系统中含量最多的内源性大麻素。2-AG作为大麻素受体1型（CB1R）和CB2R的完全激动剂，分别主要表达于脑和免疫细胞。因此，我们推测在MGL缺失的情况下，增加的2-AG浓度介导免疫细胞中的CB2R信号调节炎症反应，从而影响动脉粥样硬化的发展。我们培育了载脂蛋白E (ApoE)/MGL双敲除（DKO）小鼠，并给它们喂食西式饮食9周。尽管DKO小鼠的2-AG浓度全系统增加，但CB2R介导的信号仍然完全有效，反对CB2R脱敏。我们发现DKO小鼠的正面主动脉（1.3倍，p = 0.028）和主动脉瓣段（1.5倍，p = 0.0010）斑块形成增加。有趣的是，DKO小鼠还表现出脂质降低（12%,p = 0.031）和巨噬细胞含量降低（18%,p = 0.061），斑块内平滑肌染色升高（1.4倍，p = 0.016），纤维帽变厚（1.8倍，p = 0.0032），胶原蛋白与坏死核心区域的比例增加（2.5倍，p = 0.0003），胶原蛋白含量增加（1.6倍，p = 0.0007），这表明形成了不那么脆弱的动脉粥样硬化斑块。在DKO小鼠中，用CB2R逆激动剂治疗可防止这些作用，这表明在DKO小鼠中观察到的斑块表型源于CB2R激活。MGL的缺失会调节cb2r表达细胞中的内源性大麻素信号，从而影响动脉粥样硬化的发病机制。我们得出结论，尽管病变面积较大，但MGL的损失可改善动脉粥样硬化斑块的稳定性。因此，药物抑制MGL可能是一种新的干预措施，以减少斑块破裂。
Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis. We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation. Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture.