title: Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning.
abstract: Recent studies have suggested that autophagy plays a prosurvival role in ischemic preconditioning (IPC). This study was taken to assess the linkage between autophagy and endoplasmic reticulum (ER) stress during the process of IPC. The effects of IPC on ER stress and neuronal injury were determined by exposure of primary cultured murine cortical neurons to 30 min of OGD 24 h prior to a subsequent lethal OGD. The effects of IPC on ER stress and ischemic brain damage were evaluated in rats by a brief ischemic insult followed by permanent focal ischemia (PFI) 24 h later using the suture occlusion technique. The results showed that both IPC and lethal OGD increased the LC3-II expression and decreased p62 protein levels, but the extent of autophagy activation was varied. IPC treatment ameliorated OGD-induced cell damage in cultured cortical neurons, whereas 3-MA (5-20 mM) and bafilomycin A 1 (75-150 nM) suppressed the neuroprotection induced by IPC. 3-MA, at the dose blocking autophagy, significantly inhibited IPC-induced HSP70, HSP60 and GRP78 upregulation; meanwhile, it also aggregated the ER stress and increased activated caspase-12, caspase-3 and CHOP protein levels both in vitro and in vivo models. The ER stress inhibitor Sal (75 pmol) recovered IPC-induced neuroprotection in the presence of 3-MA. Rapamycin 50-200 nM in vitro and 35 pmol in vivo 24 h before the onset of lethal ischemia reduced ER stress and ischemia-induced neuronal damage. These results demonstrated that pre-activation of autophagy by ischemic preconditioning can boost endogenous defense mechanisms to upregulate molecular chaperones, and hence reduce excessive ER stress during fatal ischemia.
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sheng
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Liu
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.forename: Ying-Qiu
authors.initials: YQ
authors.lastname: Wu
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhang
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D002934:Cinnamates / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP
chemical_list: D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C496827:salubrinal; D051742:Transcription Factor CHOP; C025946:3-methyladenine; D053454:Caspase 12; D053148:Caspase 3; D013890:Thiourea; D005947:Glucose; D000225:Adenine; D010100:Oxygen; D020123:Sirolimus