Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice
Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice
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DOI：
10.1016/j.jnutbio.2011.02.001
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发表时间：
2012-05-01
影响因子：
5.6
通讯作者：
Berard, Annie M.
中科院分区：
文献类型：
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作者：
Chanet, Audrey;Milenkovic, Dragan;Berard, Annie M.
柚皮苷（Naringin， NAR）显示出对动脉粥样硬化发展的潜在保护作用，然而，这种作用的具体机制尚不清楚。因此，我们旨在研究NAR在不同高胆固醇血症小鼠模型中的抗动脉粥样硬化作用，并利用转录组学方法破译其在主动脉中的分子靶点。研究了两种高胆固醇血症小鼠模型，即饲喂高脂肪/高胆固醇饮食的野生型小鼠和饲喂半合成饮食的载脂蛋白e缺乏小鼠。在对照组饲粮中分别添加0.02% NAR（即营养补充）和不添加NAR，饲喂18周。补充NAR仅在喂食高脂肪/高胆固醇饮食的野生型小鼠中减少斑块进展（-41%）。与这种保护作用一致，NAR降低了血浆非高密度脂蛋白胆固醇浓度以及内皮功能障碍的生物标志物。在主动脉上进行的微阵列研究表明，编码参与细胞粘附、肌动蛋白、细胞骨架组织和细胞分裂的蛋白的基因存在差异。因此，NAR诱导的基因表达变化可能通过阻止免疫细胞在血管壁内膜的粘附和浸润以及平滑肌细胞的增殖来提示动脉粥样硬化的有限进展。体外实验进一步证实了这一假设，柚皮素能够降低单核细胞对内皮细胞的粘附，减少平滑肌细胞的增殖。总之，本研究揭示了在营养上可达到的剂量下补充NAR的抗动脉粥样硬化作用，特别是对饮食诱导的动脉粥样硬化，并描述了其在血管水平上的多靶点作用模式。(C) 2012爱思唯尔公司版权所有。
Naringin (NAR) from grapefruit has exhibited potential protective effects against atherosclerosis development However, specific mechanisms responsible for such effects are poorly understood. Thus, we aimed to investigate the antiatherogenic effects of NAR in different mouse models of hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of hypercholesterolemia, wild-type mice fed a high-fat/high-cholesterol diet and apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-cholesterol diet (-41%). Consistent with this protective effect, NAR reduced plasma non-high-density lipoprotein cholesterol concentrations as well as biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced atherosclerosis, and depicted its multitarget mode of action at the vascular level. (C) 2012 Elsevier Inc. All rights reserved.