Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning
Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning
复制标题
自噬调节缺血预处理中的内质网应激
DOI：
10.4161/auto.18673
复制
发表时间：
2012-03-01
期刊：
影响因子：
13.3
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
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作者：
Sheng, Rui;Liu, Xiao-Qian;Qin, Zheng-Hong
最近的研究表明，自噬在缺血预适应（IPC）中起着促进生存的作用。本研究旨在探讨IPC过程中自噬与内质网应激的关系。IPC对内质网应激和神经元损伤的影响通过将原代培养的小鼠皮层神经元暴露于随后的致死性OGD 24 h之前的30 min OGD来确定。采用线栓法观察缺血预处理对大鼠内质网应激和缺血性脑损伤的影响。结果表明，IPC和致死OGD均能增加LC 3-II表达，降低p62蛋白水平，但自噬激活程度不同。IPC处理改善了OGD诱导的培养皮层神经元的细胞损伤，而3-MA（5-20 mM）和巴弗洛霉素A1（75-150 nM）抑制IPC诱导的神经保护作用。阻断自噬剂量的3-MA可显著抑制IPC诱导的HSP 70、HSP 60和GRP 78表达上调，同时可聚集内质网应激，增加caspase-12、caspase-3和CHOP蛋白水平。ER应激抑制剂Sal（75 pmol）在3-MA存在下恢复IPC诱导的神经保护作用。雷帕霉素50-200 nM在体外和35 pmol在体内24小时前致命的缺血发作减少ER应激和缺血诱导的神经元损伤。这些结果表明，通过缺血预处理预激活自噬可以增强内源性防御机制，上调分子伴侣，从而减少致命性缺血期间过度的ER应激。
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 A1 (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.