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阿托伐他汀减轻巨噬细胞内质网应激及其介导的细胞凋亡

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2016年第2期
页码:
129-135
栏目:
基础研究
出版日期:
2015-11-25

文章信息/Info

Title:
Atorvastatin alleviates endoplasmic reticulum stress and apoptosis in macrophages
作者:
崔明丽; 蔡招华; 孙 哲; 孙士群; 储时春; 沈玲红; 何 奔
（上海交通大学医学院附属仁济医院心内科，上海 200127）
Author(s):
CUI Ming-li;  CAI Zhao-hua;  SUN Zhe;  SUN Shi-qun;  CHU Shi-chun;  SHEN Ling-hong;  HE Ben
(Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China)
关键词:
阿托伐他汀; 7-酮胆固醇; ER stress; 动脉粥样硬化; 小鼠巨噬细胞
Keywords:
atorvastatin;  7-ketocholesterol;  endoplasmic reticulum stress;  atherosclerosis;  oxidative stress
分类号:
R972
DOI:
-
文献标识码:
A
摘要:
目的 探讨阿托伐他汀对7-酮胆固醇（7-KC）诱导的巨噬细胞内质网应激及细胞凋亡的影响。方法 AopE-/-小鼠左肾动脉和左颈总动脉联合部分结扎建立颈动脉易损斑块模型。采用HE染色方法观察斑块病理学改变，用免疫荧光结合激光扫描共聚焦显微镜技术检测斑块中内质网应激(ER stress)相关蛋白CHOP及磷酸化PERK（p-PERK）的表达。体外培养小鼠巨噬细胞RAW264.7，给予7-KC、H2O2或联合阿托伐他汀处理后，蛋白质免疫印迹方法（Western blot）测定ER stress相关蛋白CHOP、p-PERK 、XBP-1s及凋亡相关蛋白cleaved caspase-3的表达。结果 AopE-/-小鼠颈动脉易损斑块局部ER stress相关蛋白CHOP的表达及PERK磷酸化水平明显上调；7-KC可诱导小鼠巨噬细胞ER stress，进而诱导细胞凋亡；同时，氧化应激诱导剂H2O2也可通过诱导小鼠巨噬细胞ER stress介导细胞凋亡；而阿托伐他汀可抑制7-KC和H2O2诱导的巨噬细胞ER stress及其介导的细胞凋亡。结论 ER stress可能参与AS易损斑块的形成；阿托伐他汀可通过减少细胞内氧化应激的水平，减轻巨噬细胞ER stress，从而抑制细胞凋亡。
Abstract:
AIM To investigate the effect of atorvastatin on 7-ketocholesterol (7-KC)-induced endoplasmic reticulum stress (ER stress) and apoptosis in macrophages. METHODS We generated an ApoE-/- mouse model of vulnerable carotid atherosclerotic plaque by partial ligation of the left common carotid artery and left renal artery. The pathological changes of atherosclerotic plaques were observed by hematoxylin-eosin (HE) staining and the expression level or phosphorylation status of ER stress-associated proteins (CHOP and p-PERK) were detected by immunofluorescence staining. Macrophages (murine RAW 264.7 cells) were cultured and incubated with 7-KC or H2O2 with or without pretreatment with atorvastatin. ER stress-associated proteins (CHOP, p-PERK, XBP-1s) and apoptotic protein (cleaved caspase-3) were measured by Western blotting. RESULTS Vulnerable carotid atherosclerotic plaques from ApoE-/- mice showed induction of ER stress, as indicated by elevated CHOP levels and PERK phosphorylation. Levels of CHOP expression, PERK phosphorylation and cleavage of caspase-3 were elevated after exposure RAW264.7 cells to 7-KC, as well as to the direct inducer of oxidative stress H2O2. Atorvastatin inhibited 7-KC- and H2O2-induced ER stress and apoptosis in RAW264.7 cells in vitro. CONCLUSION 7-KC and oxidative stress induce ER stress and apoptosis in macrophages in vulnerable atherosclerotic plaques. Atorvastatin inhibits ER stress and apoptosisvia reducing oxidative stress.

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备注/Memo

备注/Memo:
收稿日期：2015-04-17.
基金项目：国家自然科学基金项目资助（81370399）
通讯作者：何奔，教授，主要从事冠状动脉粥样硬化基础与临床研究 Email:rjheben@126.com
作者简介：崔明丽，硕士生 Email:qycuiml0403@163.com
更新日期/Last Update: 2016-04-25