Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury:PERK as a potential target for interventionOA
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
Ju Zheng;Yixin Li;Ting Zhang;Yanlin Fu;Peiyan Long;Xiao Gao;Zhengwei Wang;Zhizhong Guan;Xiaolan Qi;Wei Hong;Yan Xiao;
Key Laboratory of Endemic and Ethnic Diseases,Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou Province,Guizhou Medical University,Guiyang,Guizhou Province,China Guizhou Center for Disease Control and Prevention,Guiyang,Guizhou Province,ChinaDepartment of Histology and Embryology,Guizhou Medical University,Guiyang,Guizhou Province,ChinaKey Laboratory of Endemic and Ethnic Diseases,Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou Province,Guizhou Medical University,Guiyang,Guizhou Province,ChinaKey Laboratory of Endemic and Ethnic Diseases,Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou Province,Guizhou Medical University,Guiyang,Guizhou Province,China Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry,Guiyang,Guizhou Province,China
临床医学
apoptosisATF4autophagyC/EBP homologous proteincerebral ischemia/reperfusion injuryeIF2αendoplasmic reticulum stressPERK
《Neural Regeneration Research》 2025 (005)
P.1455-1466 / 12
supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG);Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH);Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX);Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
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