Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice.
Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice.
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DOI：
10.1155/2013/847310
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Yang H
中科院分区：
文献类型：
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作者：
Zhou L;Yang D;Wu DF;Guo ZM;Okoro E;Yang H
我们以前报道过载脂蛋白（apo）B48携带脂蛋白（E−/B48脂蛋白）从apoE敲除小鼠（apoE −/−）中获得，这种脂蛋白能将小鼠巨噬细胞转化为泡沫细胞，并增强真核翻译起始因子2α（eIF-2α）的磷酸化。此外，eIF-2α磷酸化抑制剂2-氨基嘌呤（2-AP）可减弱E−/B48脂蛋白诱导的泡沫细胞形成。本报告研究了2-AP对apoE −/−小鼠动脉粥样硬化的影响。我们的结果表明，在接受或不接受2-AP治疗的apoE −/−小鼠中，食物摄入量、体重、血浆胆固醇和甘油三酯水平相当。然而，与未处理的对照apoE −/−小鼠相比，2-AP处理的apoE −/−小鼠主动脉窦中动脉粥样硬化病变的平均大小以及整个主动脉的表面积分别减少了约55%和39%。此外，与未治疗的对照apoE −/−小鼠相比，2-AP治疗的apoE −/−小鼠显示其主动脉样本中葡萄糖调节蛋白78（GRP 78）和磷酸化eIF-2α的水平显著降低。这些观察结果表明，内质网应激是apoE −/−小鼠动脉粥样硬化发展的一种因果机制，可以开发使用eIF-2α磷酸化抑制剂（如2-AP）预防或治疗动脉粥样硬化的治疗策略。
We previously reported that the apolipoprotein (apo) B48-carrying lipoproteins obtained from apoE knockout (apoE −/−) mice, so called E−/B48 lipoproteins, transformed mouse macrophages into foam cells and enhanced the phosphorylation of eukaryotic translation initiation factor 2α (eIF-2α). Furthermore, the eIF-2α phosphorylation inhibitor, 2-aminopurine (2-AP), attenuated E−/B48 lipoprotein-induced foam cell formation. The present report studied the effect of 2-AP on atherosclerosis in apoE −/− mice. Our results showed that the level of food intake, bodyweight, plasma cholesterol, and triglycerides was comparable in apoE −/− mice treated with or without 2-AP. However, the mean size of atherosclerotic lesions in the aorta sinus as well as the surface area of the entire aorta of 2-AP-treated apoE −/− mice were reduced by about 55% and 39%, respectively, compared to samples from untreated control apoE −/− mice. In addition, the 2-AP-treated apoE −/− mice showed a significant decrease in glucose-regulated protein 78 (GRP78) and phosphorylated eIF-2α in their aortic samples as compared to levels in untreated control apoE −/− mice. These observations suggest that endoplasmic reticulum stress is a causal mechanism for the development of atherosclerosis in apoE −/− mice and that therapeutic strategies can be developed for using eIF-2α phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis.