Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS
Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS
复制标题
内质网应激通过改善细胞内ROS来调节人SH-SY5Y细胞中氧糖剥夺诱导的parthanatos
DOI：
10.1111/cns.12771
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发表时间：
2018
影响因子：
5.5
通讯作者：
Ge Peng-Fei
中科院分区：
文献类型：
--
作者：
Wang Hai-Feng;Wang Zong-Qi;Ding Ye;Piao Mei-Hua;Feng Chun-Sheng;Chi Guang-Fan;Luo Yi-Nan;Ge Peng-Fei
目的已证明内质网（ER）应激可通过激活细胞凋亡来调节缺血性损伤引起的神经元死亡，但ER应激是否参与细胞凋亡的调节仍不清楚，一种新型的程序性细胞死亡，其特征是PARP-1过度激活和PAR聚合物的细胞内积累。结果缺氧缺糖诱导SH-SY 5 Y细胞呈时间依赖性死亡，并伴有PARP-1表达上调、PAR聚合物积聚、线粒体膜电位下降和AIF核转位。PARP-1及其特异性抑制剂3AB的药理学抑制挽救了OGD诱导的细胞死亡，并防止了PAR聚合物积累、线粒体去极化和AIF易位到细胞核中。当用SiRNA基因敲除PARP-1时，可以发现类似的结果。这表明OGD触发了SH-SY 5 Y细胞中的死亡。然后，我们发现用抗氧化剂NAC抑制ROS的过度产生明显减弱了OGD诱导的SH-SY 5 Y细胞的死亡，表明ROS调节OGD诱导的死亡。此外，OGD还诱导ER应激相关蛋白的上调。用化学伴侣4-PBA或海藻糖减轻ER应激显著抑制了OGD诱导的ROS过度产生、PARP-1上调、PAR聚合物积累和AIF核积累以及SH-SY 5 Y细胞中的细胞死亡。结论内质网应激通过改善细胞内ROS来调节OGD诱导的人SH-SY 5 Y细胞死亡。
AimsEndoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear whether ER stress participates in regulation of parthanatos, a new type of programmed cell death characterized by PARP‐1 overactivation and intracellular accumulation of PAR polymer.Methodswe used oxygen‐glucose deprivation (OGD) and human SH‐SY5Y cells to simulate neuronal damage caused by ischemia.ResultsOxygen‐glucose deprivation induced time‐dependent death in SH‐SY5Y cells, which was accompanied with upregulation of PARP‐1, accumulation of PAR polymer, decline of mitochondrial membrane potentials and nuclear translocation of AIF. Pharmacological inhibition of PARP‐1 with its specific inhibitor 3AB rescued OGD‐induced cell death, as well as prevented PAR polymer accumulation, mitochondrial depolarization, and AIF translocation into nucleus. Similar results could be found when PARP‐1 was genetically knocked down with SiRNA. These indicated that OGD triggered parthanatos in SH‐SY5Y cells. Then, we found inhibition of overproduction of ROS with antioxidant NAC attenuated obviously OGD‐induced parthanatos in SH‐SY5Y cells, suggesting ROS regulated OGD‐induced parthanatos. Additionally, OGD also induced upregulation of ER stress‐related proteins. Mitigation of ER stress with chemical chaperone 4‐PBA or trehalose suppressed significantly OGD‐induced overproduction of ROS, PARP‐1 upregulation, PAR polymer accumulation, and nuclear accumulation of AIF, and cell death in SH‐SY5Y cells.ConclusionEndoplasmic reticulum stress regulates OGD‐induced parthanatos in human SH‐SY5Y cells via improvement of intracellular ROS.