Downregulation of miR-181b in mouse brain following ischemic stroke induces neuroprotection against ischemic injury through targeting heat shock protein A5 and ubiquitin carboxyl-terminal hydrolase isozyme L1

被引：112

作者：

Peng, Zhifeng ^{[2
,3
,4
]}

Li, Jiefei ^{[2
,3
]}

Li, Yun ^{[2
,3
]}

Yang, Xuan ^{[2
,3
]}

Feng, Sujuan ^{[2
,3
]}

Han, Song ^{[2
,3
]}

Li, Junfa ^{[1
,2
,3
]}

机构：

[1] Capital Med Univ, Beijing Inst Brain Disorders, Dept Neurobiol, 10 You An Men Wai Xi Tou Tiao, Beijing 100069, Peoples R China

[2] Capital Med Univ, Dept Neurobiol, Beijing 100069, Peoples R China

[3] Capital Med Univ, Beijing Inst Brain Disorders, Beijing 100069, Peoples R China

[4] Shanxi Datong Univ, Sch Med, Dept Physiol, Datong, Peoples R China

来源：

JOURNAL OF NEUROSCIENCE RESEARCH | 2013年 / 91卷 / 10期

基金：

中国国家自然科学基金;

关键词：

stroke; hypoxia; ischemia; hypoxic preconditioning; protein kinase C; miRNA; ENDOPLASMIC-RETICULUM STRESS; CEREBRAL-ARTERY OCCLUSION; TRANSIENT FOCAL ISCHEMIA; NEURODEGENERATIVE DISEASES; MEMBRANE TRANSLOCATION; EXPRESSED MICRORNAS; PROTEASOME SYSTEM; KINASE-C; CELLS; MICE;

D O I：

10.1002/jnr.23255

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Understanding the molecular mechanism of cerebral hypoxic preconditioning (HPC)-induced endogenous neuroprotection may provide potential therapeutic targets for ischemic stroke. By using bioinformatics analysis, we found that miR-181b, one of 19 differentially expressed miRNAs, may target aconitate hydratase (ACO2), heat shock protein A5 (HSPA5), and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) among 26 changed protein kinase C isoform-specific interacting proteins in HPC mouse brain. In this study, the role of miR-181b in oxygen-glucose deprivation (OGD)-induced N2A cell ischemic injury in vitro and mouse middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury in vivo, and its regulation of ACO2, HSPA5, and UCHL1 were further determined. We found that miR-181b expression levels significantly decreased in mouse brain following MCAO and in OGD-treated N2A cells. Up- and downregulation of miR-181b by transfection of pre- or anti-miR-181b could negatively regulate HSPA5 and UCHL1 (but not ACO2) protein levels as well as N2A cell death and programmed cell death in OGD-treated N2A cells. By using a T7 promoter-driven control dual luciferase assay, we confirmed that miR-181b could bind to the 3-untranslated rergions of HSPA5 and UCHL1 mRNAs and repress their translations. miR-181b antagomir reduced caspase-3 cleavage and neural cell loss in cerebral ischemic cortex and improved neurological deficit of mice after MCAO. In addition, HSPA5 and UCHL1 short interfering RNAs (siRNAs) blocked anti-miR-181b-mediated neuroprotection against OGD-induced N2A cell injury in vitro. These results suggest that the downregulated miR-181b induces neuroprotection against ischemic injury through negatively regulating HSPA5 and UCHL1 protein levels, providing a potential therapeutic target for ischemic stroke. (c) 2013 Wiley Periodicals, Inc.

引用

页码：1349 / 1362

页数：14