The phosphokinase activity of IRE1α prevents the oxidative stress injury through miR-25/Nox4 pathway after ICH

作者全名："Liao, Yuhui; Huang, Juan; Wang, Zhenhua; Yang, Zhengyu; Shu, Yue; Gan, Shengwei; Wang, Zhixu; Lu, Weitian"

作者地址："[Liao, Yuhui; Huang, Juan; Wang, Zhenhua; Yang, Zhengyu; Shu, Yue; Gan, Shengwei; Wang, Zhixu; Lu, Weitian] Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing 400016, Peoples R China; [Liao, Yuhui; Huang, Juan; Wang, Zhenhua; Yang, Zhengyu; Shu, Yue; Gan, Shengwei; Wang, Zhixu; Lu, Weitian] Chongqing Med Univ, Inst Neurosci, Basic Med Coll, Chongqing, Peoples R China; [Liao, Yuhui] Sichuan Univ Arts & Sci, Med Coll, Dazhou, Peoples R China"

通信作者："Lu, WT (通讯作者)，Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing 400016, Peoples R China."

来源：CNS NEUROSCIENCE & THERAPEUTICS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001108527300001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：intracerebral hemorrhage; IRE1 alpha; miR-25-3p; Nox4; oxidative stress

摘要："Background: Endoplasmic reticulum (ER) stress and oxidative stress are the major pathologies encountered after intracerebral hemorrhage (ICH). Inositol-requiring enzyme-1 alpha (IRE1 alpha) is the most evolutionarily conserved ER stress sensor, which plays a role in monitoring and responding to the accumulation of unfolded/misfolded proteins in the ER lumen. Recent studies have shown that ER stress is profoundly related to oxidative stress in physiological or pathological conditions. The purpose of this study was to investigate the role of IRE1 alpha in oxidative stress and the potential mechanism.Methods: A mouse model of ICH was established by autologous blood injection. The IRE1 alpha phosphokinase inhibitor KIRA6 was administrated intranasally at 1 h after ICH, antagomiR-25 and agomiR-25 were injected intraventricularly at 24 h before ICH. Western blot analysis, RT-qPCR, immunofluorescence staining, hematoma volume, neurobehavioral tests, dihydroethidium (DHE) staining, H2O2 content, brain water content, body weight, Hematoxylin and Eosin (HE) staining, Nissl staining, Morris Water Maze (MWM) and Elevated Plus Maze (EPM) were performed.Results: Endogenous phosphorylated IRE1 alpha (p-IRE1 alpha), miR-25-3p, and Nox4 were increased in the ICH model. Administration of KIRA6 downregulated miR-25-3p expression, upregulated Nox4 expression, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, reduced body weight, aggravated spatial learning and memory deficits, and increased anxiety levels. Then antagomiR-25 further upregulated the expression of Nox4, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, whereas agomiR-25 reversed the effects promoted by KIRA6.Conclusion: The IRE1 alpha phosphokinase activity is involved in the oxidative stress response through miR-25/Nox4 pathway in the mouse ICH brain."

基金机构：National Natural Science Foundation of China

基金资助正文：Not applicable.