Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis
Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis
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DOI：
10.1016/j.atherosclerosis.2008.12.040
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发表时间：
2009-08-01
期刊：
影响因子：
5.3
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
--
作者：
Montecucco, Fabrizio;Matias, Isabel;Di Marzo, Vincenzo
在这项研究中，我们分析了内源性大麻素和相关分子在小鼠动脉粥样硬化发展过程中的可能调节。野生型和载脂蛋白E基因敲除（ApoE（-/-））小鼠喂食正常食物或高胆固醇饮食8-12周，并通过液相色谱-质谱法测量组织内源性大麻素水平。我们发现，与正常饲料喂养的ApoE（-/-）小鼠或胆固醇喂养的野生型小鼠相比，高胆固醇饮食喂养12周的ApoE（-/-）小鼠的腹主动脉和内脏脂肪组织（VAT）中2-AG水平升高。在8周的饮食后，2-AG水平没有观察到显著差异，并且在任何组中都没有发现花生四烯酸水平的变化。具有抗炎或抗脂肪生成特性的花生四烯酸相关介质棕榈酰乙醇胺（PEA）和油酰乙醇胺（OEA）的水平分别仅在VAT或两种组织中降低或升高。动脉粥样硬化病变内的巨噬细胞表达内源性大麻素和OEA/PEA降解酶。在体外，2-AG和OEA在0.3-1 μ M诱导单核细胞迁移，这对应于在红细胞中观察到的水平。PEA 1 μ M也诱导单核细胞迁移，但抵消了2-AG的效果，而OEA增强它。增强2-AG水平在先进的动脉粥样硬化病变可能会引发炎症过程中招募更多的炎症细胞和诱导细胞外基质降解通过CB 2受体，这种可能性是支持在体外，但不是在体内的实验与CB 2拮抗剂，SR 144528。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
In this study we analysed the possible modulation of endocannabinoids and related molecules during atherosclerosis development in mice. Wild-type and apolipoprotein E knockout (ApoE(-/-)) mice were fed either normal chow or high-cholesterol diet for 8-12 weeks, and tissue endocannabinoid levels were measured by liquid chromatography-mass spectrometry. We found increased levels of 2-AG in aortas and visceral adipose tissue (VAT) of ApoE(-/-) mice fed on high-cholesterol diet for 12 weeks as compared to ApoE(-/-) mice fed on normal chow or wild-type mice fed on cholesterol. No significant difference in 2-AG levels was observed after 8 weeks of diet, and no changes in anandamide levels were found in any group. The levels of the anandamide-related mediators with anti-inflammatory or anti-lipogenic properties, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), decreased or increased only in VAT or in both tissues, respectively. Endocannabinoid- and OEA/PEA-degrading enzymes were expressed by macrophages within atherosclerotic lesions. In vitro, 2-AG and OEA-induced monocyte migration at 0.3-1 mu M, which corresponds to the levels observed in aortas. PEA 1 mu M also induced monocyte migration but counteracted the effect of 2-AG, whereas OEA enhanced it. Enhanced 2-AG levels in advanced atherosclerotic lesions may trigger the inflammatory process by recruiting more inflammatory cells and inducing extracellular matrix degradation via CB2 receptors, and this possibility was supported in vitro but not in vivo by experiments with the CB2 antagonist, SR144528. (C) 2009 Elsevier Ireland Ltd. All rights reserved.