中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (6): 1024-1030.doi: 10.4103/1673-5374.300455

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

microRNA-670可通过Yap通路加剧脑缺血再灌注损伤

  

  • 出版日期:2021-06-15 发布日期:2020-12-31
  • 基金资助:

    国家自然科学基金项目(817712718190253782001475);中国医科大学盛京医院科学基金(M0124);中国医科大学盛京医院“345人才工程”;辽宁省自然科学基金(20180550913

MicroRNA-670 aggravates cerebral ischemia/reperfusion injury via the Yap pathway 

Shi-Jia Yu1, Ming-Jun Yu2, Zhong-Qi Bu1, Ping-Ping He1, Juan Feng1, *   

  1. 1 Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China;  2 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2021-06-15 Published:2020-12-31
  • Contact: Juan Feng, MD, PhD, fengjuandr@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81771271 (to JF), 81902537 (to MJY), 82001475 (to SJY); a Scientific Fund of Shengjing Hospital of China Medical University, No. M0124 (to SJY); the “345 Talent Project” from Shengjing Hospital of China Medical University (to SJY); the Natural Science Foundation of Liaoning Province of China, No. 20180550913 (to MJY).

摘要:

细胞凋亡是脑缺血再灌注损伤中最重要的程序性细胞死亡之一。microRNA被认为在调节脑缺血再灌注损伤中起着重要作用,但是miR-670是否可调节脑缺血再灌注损伤中的细胞生长和死亡及其机制尚不明确。实验建立了短暂大脑中动脉闭塞小鼠模型以及氧剥夺复氧N2a细胞模型,以在体内外探索脑缺血再灌注损伤损伤过程中miR-670作用的潜在分子机制。结果显示脑缺血再灌注损伤,miR-670表达明显增加。以miR-670拮抗剂(antagomir)抑制miR-670表达后,脑缺血再灌注损伤诱导的神经元凋亡明显减少。而miR-670模拟物(Agomir)过表达miR-670,则加剧神经元的凋亡。此外还发现miR-670可通过磷酸化Yap通路抑制Yap表达,从而加剧神经元凋亡和神经功能缺损。而抑制miR-670则有助于减少脑神经元凋亡后的神经功能障碍。这些结果表明microRNA-670通过Yap通路加剧脑缺血再灌注损伤,因而可能成为未来治疗脑缺血再灌注损伤的潜在靶点。研究于2017227日经中国医科大学动物伦理委员会批准,批准号IRB 2017PS035K

https://orcid.org/0000-0002-1815-7036 (Juan Feng)

关键词: 脑缺血再灌注, 非编码RNA, 微小RNA, miR-670, 细胞凋亡, 神经元, 神经功能, 通路

Abstract: Apoptosis is an important programmed cell death process involved in ischemia/reperfusion injury. MicroRNAs are considered to play an important role in the molecular mechanism underlying the regulation of cerebral ischemia and reperfusion injury. However, whether miR-670 can regulate cell growth and death in cerebral ischemia/reperfusion and the underlying mechanism are poorly understood. In this study, we established mouse models of transient middle artery occlusion and Neuro 2a cell models of oxygen-glucose deprivation and reoxygenation to investigate the potential molecular mechanism by which miR-670 exhibits its effects during cerebral ischemia/reperfusion injury both in vitro and in vivo. Our results showed that after ischemia/reperfusion injury, miR-670 expression was obviously increased. After miR-670 expression was inhibited with an miR-670 antagomir, cerebral ischemia/reperfusion injury-induced neuronal death was obviously reduced. When miR-670 overexpression was induced by an miR-670 agomir, neuronal apoptosis was increased. In addition, we also found that miR-670 could promote Yap degradation via phosphorylation and worsen neuronal apoptosis and neurological deficits. Inhibition of miR-670 reduced neurological impairments after cerebral ischemia/reperfusion injury. These results suggest that microRNA-670 aggravates cerebral ischemia/reperfusion injury through the Yap pathway, which may be a potential target for treatment of cerebral ischemia/reperfusion injury. The present study was approved by the Institutional Animal Care and Use Committee of China Medical University on February 27, 2017 (IRB No. 2017PS035K).

Key words: apoptosis, cerebral ischemia and reperfusion injury, microRNA, miR-670, neurological function, neuron, non-coding RNA, pathway