瑞舒伐他汀通过调控UCP2-SIRT3通路减轻脑缺血/再灌注对神经元线粒体的损伤  

Rosuvastatin relieves neuronal mitochondrial damage by regulating UCP2-SIRT3 pathway after cerebral ischemia/reperfusion

作　　者：董雪佳 江名芳[2] 包立道 DONG Xue-jia;JIANG Ming-fang;BAO Li-dao(Graduate School,Inner Mongolia Medical University,Hohhot 010058,China;Dept of Neurology,Affiliated Hospital,Inner Mongolia Medical University,Hohhot 010059,China;Dept of Pharmacology,School of Basic Medical Sciences,Inner Mongolia Medical University,Hohhot 010110,China)

机构地区：[1]内蒙古医科大学研究生院,内蒙古呼和浩特010058 [2]内蒙古医科大学附属医院神经内科,内蒙古呼和浩特010059 [3]内蒙古医科大学基础医学院药理学教研室,内蒙古呼和浩特010110

出　　处：《中国药理学通报》2021年第1期52-61,共10页Chinese Pharmacological Bulletin

基　　金：内蒙古自治区自然科学基金项目(No 2020MS08197);内蒙古医科大学附属医院博士启动金项目(No NYFY BS2018);内蒙古自治区科技计划项目(No 201702144)。

摘　　要：目的探讨瑞舒伐他汀(rosuvastatin,RS)通过UCP2-SIRT3信号通路在脑缺血/再灌注(CIR)神经元线粒体损伤中的作用及其机制。方法建立SH-SY5Y细胞的脑梗死再灌注模型(OGD/R),给予不同浓度RS(40和2.5μmol·L^-1)分别处理,观察两组中细胞增殖和凋亡的变化及UCP2和SIRT3分子的表达;构建UCP2沉默细胞系,研究不同浓度RS对UCP2沉默前后细胞形态和线粒体膜电位的影响、以及SIRT3分子、线粒体外膜异位酶20(TOMM20)和线粒体合成相关蛋白(Drp1、Opa1和PGC1)的表达变化。结果RS能提高OGD/R细胞的存活率、抑制细胞凋亡、改变细胞形态、稳定细胞线粒体膜电位;增加OGD/R细胞中UCP2、SIRT3分子和TOMM20蛋白表达,并诱导Drp1和Opa1 mRNA的表达,抑制PGC1 mRNA的表达;沉默UCP2后能明显降低OGD/R细胞的存活率及TOMM20蛋白的表达,降低Drp1和Opa1 mRNA的表达,使PGC1 mRNA的表达增加。结论RS通过调控UCP2-SIRT3通路减轻CIR对神经元线粒体的损伤,发挥神经细胞保护作用。Aim To explore the biological role and related mechanism of rosuvastatin(RS)in mitochondrial damage of neurons after cerebral ischemia/reperfusion(CIR)through UCP2-SIRT3 signaling pathway.Methods Human neuroblastoma cell(SH-SY5Y cell)cerebral infarction reperfusion model(OGD/R)was established,different concentrations of RS40 and 2.5(mol·L^-1)were given for treatment,respectively.The changes of cell proliferation and apoptosis and the expression of UCP2 and SIRT3 molecules in the two groups were observed;UCP2 silencing cell line was constructed to study the effect of different concentrations of RS on OGD/R cell morphology and mitochondrial membrane potential before and after UCP2 silencing,the expression changes of SIRT3 molecule and mitochondrial outer memberance ectopic enzyme 20(TOMM20)in OGD/R cells,and the genes related to mitochondrial synthesis(PGC1,Drp1 and Opa1)expression changes,and then the role and mechanism of RS to protect nerve cells from OGD/R damage was explored.Results RS significantly improved the survival rate of OGD/R cells,inhibited the apoptosis of OGD/R cells,changed the morphology of OGD/R cells,promoted cell proliferation,antagonized the decrease in mitochondrial membrane potential of OGD/R cells and improved cell status.It also increased the expression of UCP2,SIRT3 and TOMM20 protein in OGD/R cells,induced the expression of Drp1 and Opa1 mRNA,and inhibited the expression of PGC1 mRNA.Silencing UCP2 could significantly reduce the survival rate of OGD/R cells and the expression of TOMM20 protein,decrease the expression of Drp1 and Opa1 mRNA,and significantly increase the expression of PGC1 mRNA.Conclusions Rosuvastatin reduces the damage of neuron mitochondria by cerebral ischemia/reperfusion through regulating UCP2-SIRT3 pathway,exerting a protective effect on neurons.

关 键 词：瑞舒伐他汀 脑缺血/再灌注 UCP2/SIRT3通路 线粒体损伤 TOMM20 Drp1 Opal 

分 类 号：R329.24[医药卫生—人体解剖和组织胚胎学] R329.25[医药卫生—基础医学]