中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (5): 779-786.doi: 10.4103/1673-5374.206649

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

激活素A对内质网应激介导PC12细胞凋亡和自噬的神经保护

  

  • 收稿日期:2017-04-20 出版日期:2017-05-15 发布日期:2017-05-15
  • 基金资助:

    中国国家自然科学基金项目（81671159, 81371298），吉林省科技发展项目（20160101099JC, 20160101073JC），吉林省卫计委青年科研项目（2014Q022），吉林大学白求恩医学中心前沿交叉学科项目（2013107028），吉林大学白求恩医学中心青年项目（2013207052）

Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death

Long-xing Xue1, Hong-yu Liu1, Yang Cui1, Yue Dong1, Jiao-qi Wang1, Qiu-ye Ji2, Jin-ting He1, Min Yao1, Ying-ying Wang1, Yan-kun Shao1, Jing Mang1, Zhong-xin Xu1   

  1. 1 Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China; 2 Research Center, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
  • Received:2017-04-20 Online:2017-05-15 Published:2017-05-15
  • Contact: Jing Mang or Zhong-xin Xu, mangjing@jlu.edu.cn or xuzhongxin999@aliyun.com.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81671159, No. 81371298; a grant from the Development of Science and Technology of Jilin Province of China, No. 20160101099JC, No. 20160101073JC; a grant from the Youth Scientific Research of Health and Family Planning Commission in Jilin Province of China, No. 2014Q022; a grant from the Frontier Interdiscipline Program of Norman Bethune Health Science Center of Jilin University of China, No. 2013107028; a grant from the Young Scholars Program of Norman Bethune Health Science Center of Jilin University of China, No. 2013207052.

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摘要：

既往研究发现激活素A可抑制线粒体/细胞色素c途径介导的细胞凋亡而发挥神经保护作用，但遗憾的是专家们并未明确内质网应激介导细胞死亡的作用机制。鉴于内质网应激介导的细胞凋亡和自噬参与脑缺血和神经退行性疾病，实验以内质网应激诱导剂毒胡萝卜素诱导神经细胞样PC12细胞死亡，以外源激活素A进行干预，见激活素A可显著抑制毒胡萝卜素诱导的凋亡细胞形态变化以及凋亡相关蛋白(CHOP，cleaved-caspase-12及cleaved-caspase-3)和自噬生物标志物(Beclin-1和LC3II)的表达，还下调毒胡萝卜素诱导的内质网应激相关蛋白肌醇需求酶1、肿瘤坏死因子受体相关因子2、凋亡信号调节因子1、JNK、p38的表达，但其抑制毒胡萝卜素诱导的细胞死亡呈浓度依赖性。结果表明激活素A通过抑制肌醇需求酶1-肿瘤坏死因子受体相关因子2-凋亡信号调节因子1-JNK/p38信号通路，发挥了减轻内质网应激介导的神经细胞凋亡和自噬性细胞死亡的作用。

ORCID:0000-0003-3154-9218(Jing Mang);0000-0001-7066-7159(Zhong-xin Xu)

关键词: 神经再生, 激活素A , 内质网应激, 细胞凋亡, 自噬, JNK , p38

Abstract:

Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER) stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP) and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3), and downregulated the expression of thapsigargin-induced ER stress-associated proteins [inositol requiring enzyme-1 (IRE1), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38]. The inhibition of thapsigargin-induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1-TRAF2-ASK1-JNK/p38 cascade.

Key words: nerve regeneration, Activin A, endoplasmic reticulum stress, apoptosis, autophagy, c-Jun N-terminal kinase, p38, neural regeneration