Atorvastatin Inhibits Homocysteine-Induced Endoplasmic Reticulum Stress through Activation of AMP-Activated Protein Kinase
Atorvastatin Inhibits Homocysteine-Induced Endoplasmic Reticulum Stress through Activation of AMP-Activated Protein Kinase
复制标题
阿托伐他汀通过激活 AMP 激活的蛋白激酶抑制同型半胱氨酸诱导的内质网应激
DOI：
10.1111/j.1755-5922.2011.00287.x
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发表时间：
2012-01-01
影响因子：
3.1
通讯作者：
Lu, Guoping
中科院分区：
文献类型：
--
作者：
Jia, Fang;Wu, Chunfang;Lu, Guoping
目的：越来越多的证据表明，内质网（ER）应激在动脉粥样硬化的发生和发展中起着重要作用。已知阿托伐他汀对心血管系统具有多效性作用。本研究旨在探讨阿托伐他汀对同型半胱氨酸（Hcy）诱导的内质网应激激活的影响及其与腺苷酸活化蛋白激酶（AMPK）的关系。方法与结果：给载脂蛋白E缺陷（apoE（-/-））小鼠注射甲硫氨酸或阿托伐他汀，2个月后处死，进行血浆检测和免疫组化分析。为进一步研究其作用机制，将人脐静脉内皮细胞（HUVECs）与不同浓度的Hcy共同孵育1h，或500 μ mol/L Hcy共同孵育124 h。此外，我们在存在或不存在阿托伐他汀、5-氨基-4-咪唑甲酰胺核苷-1-β-D-呋喃核糖苷（AICAR）、AMPK激动剂和表达AMPK显性阴性突变体的AMPK-DN的情况下，用Hcy挑战HUVEC。通过实时PCR和Western印迹分析测量ER应激标记物的表达水平。我们的数据显示，阿托伐他汀预防同型半胱氨酸诱导的ER应激高同型半胱氨酸血症小鼠的主动脉根部。体外研究表明阿托伐他汀也能抑制Hcy诱导的HUVECs内质网应激。AICAR的作用与阿托伐他汀相似，可被AMPK-DN拮抗。结论：阿托伐他汀在体内外均能抑制Hcy诱导的内质网应激。阿托伐他汀对Hcy诱导的血管损伤的保护作用是通过AMPK激活介导的。
Aim: Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a fundamental role in the initiation and development of atherosclerosis. Atorvastatin is known to exert pleiotropic effects on cardiovascular system. This study was designed to examine the effect of atorvastatin on homocysteine (Hcy)-induced activation of ER stress and the potential mechanisms regarding AMP-activated protein kinase (AMPK). Methods and results: Apolipoprotein E-deficient (apoE(-/-)) mice were administrated with methionine or atorvastatin and sacrificed 2 months later for plasma tests and immunohistochemical analysis. To further study the mechanisms, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of Hcy for 1 h, or 500 mu mol/L Hcy for 124 h. Furthermore, we challenged HUVECs with Hcy in the presence or absence of atorvastatin, 5-amino-4-imidazolecarboxamide riboside-l-beta-D-ribofuranoside (AICAR), an AMPK agonist, and AMPK-DN that expressed a dominant-negative mutant of AMPK. Expression levels of ER stress markers were measured by real-time PCR and Western blot analysis. Our data revealed that atorvastatin prevented Hcy-induced ER stress in the aortic roots of hyperhomocysteinemic mice. In vitro study showed atorvastatin suppressed Hcy-induced ER stress in HUVECs as well. AICAR is found to have the same effect as that of atorvastatin, which could be antagonized by AMPK-DN. Conclusions: Atorvastatin inhibits Hcy-induced ER stress both in vitro and in vivo. The protective effect of atorvastatin against Hcy-induced vascular injury is mediated by AMPK activation.