Associations between autophagy, the ubiquitin-proteasome system and endoplasmic reticulum stress in hypoxia-deoxygenation or ischemia-reperfusion
Associations between autophagy, the ubiquitin-proteasome system and endoplasmic reticulum stress in hypoxia-deoxygenation or ischemia-reperfusion
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DOI：
10.1016/j.ejphar.2016.08.026
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发表时间：
2016-11-15
影响因子：
5
通讯作者：
Geng, Qing
中科院分区：
文献类型：
--
作者：
Fan, Tao;Huang, Zhixin;Geng, Qing
自噬的激活已被证明在缺氧再氧化（H/R）诱导的脑损伤中发挥保护作用。本研究旨在探讨蛋白酶体抑制剂（MG-132）、蛋白酶体启动子（阿霉素，ADM）、自噬抑制剂（3-甲基腺嘌呤，3-MA）和自噬启动子（雷帕霉素，Rap）预处理是否以及如何影响内质网应激（ERS）、泛素-蛋白酶体系统（UPS）、自噬、炎症和细胞凋亡。在h /R处理后2、4和6 h， MG-132预处理降低了泛素蛋白和26S蛋白酶体的活性，ADM预处理提高了泛素蛋白和26S蛋白酶体的活性。MG-132预处理导致自噬相关基因、内质网应激相关基因和I kappa B表达升高，NF-kappa B和caspase-3表达降低。ADM预处理导致自噬相关基因、ers相关基因和I kappa B表达降低，NF-kappa B和caspase-3表达升高。3-MA预处理降低了自噬相关基因、自噬与UPS相关基因以及凋亡相关基因的表达，而Rap预处理在h /R处理后2 h、4 h和6 h增加了凋亡相关基因的表达。在体内，ADM、MG-132、3-MA或Rap预处理后再缺血再灌注（PR）处理的大鼠也有类似的变化。蛋白酶体抑制预处理增强了自噬和内质网应激，减少了细胞凋亡和炎症反应。自噬促进预处理也表现出类似的变化。蛋白酶体抑制剂和自噬启动子的联合可能为治疗H/R或I/R损伤相关疾病提供了一种新的可能的治疗方法。(C) 2016 Elsevier B.V.版权所有
The activation of autophagy has been demonstrated to exert protective roles during hypoxia-reoxygenation (H/R)-induced brain injuries. This study aimed to investigate whether and how preconditioning with a proteasome inhibitor (MG-132), a proteasome promoter (Adriamycin, ADM), an autophagy inhibitor (3-methyladenine, 3-MA) and an autophagy promoter (Rapamycin, Rap) affected endoplasmic reticulum stress (ERS), the ubiquitin-proteasome system (UPS), autophagy, inflammation and apoptosis. Ubiquitin protein and 26S proteasome activity levels were decreased by MG-132 pretreatment but increased by ADM pretreatment at 2 h, 4 h and 6 h following H/R treatment. MG-132 pretreatment led to the increased expression of autophagy-related genes, ER stress-associated genes and I kappa B but decreased the expression levels of NF-kappa B and caspase-3. ADM pretreatment led to the decreased expression of autophagy-related genes, ERS-associated genes and I kappa B but increased the expression of NF-kappa B and caspase-3. Pretreatment with 3-MA reduced the expression of autophagy-related genes, autophagy and UPS co-related genes, as well as apoptosis-related although the latter was increased by Rap pretreatment at 2 h, 4 h and 6 h following H/R treatment. In vivo, pretreatment of rats with ADM, MG-132, 3-MA or Rap followed by ischemia-reperfusion (PR) treatment resulted in similar changes. Proteasome inhibition preconditioning strengthened autophagy and ER stress but decreased apoptosis and inflammation. Autophagy promotion preconditioning exhibited similar changes. The combination of a proteasome inhibitor and an autophagy promoter might represent a new possible therapy to treat H/R or I/R injury-related diseases. (C) 2016 Elsevier B.V. All rights reserved.