中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1734-1742.doi: 10.4103/1673-5374.360249

• 原著:退行性病与再生 • 上一篇    下一篇

敲低NADPH氧化酶4可减轻脑出血后线粒体氧化应激和神经元焦亡

  

  • 出版日期:2023-08-15 发布日期:2023-02-23
  • 基金资助:
    国家自然科学基金项目（81671125）；广东省自然科学基金项目（2021A1515011115）；广州市科技计划项目（202102010346）

Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage

Bo-Yun Ding1, #, Chang-Nan Xie2, #, Jia-Yu Xie1, Zhuo-Wei Gao3, Xiao-Wei Fei4, En-Hui Hong1, Wen-Jin Chen5, Yi-Zhao Chen1, 6, *   

  1. 1Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, Guangdong Province, China; 2Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; 3Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China; 4Department of Neurosurgery, Xijing Hospital, Air Force Military Medical University, Xi’an, Shaanxi Province, China; 5Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong Province, China; 6Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, China
  • Online:2023-08-15 Published:2023-02-23
  • Contact: Yi-Zhao Chen, PhD, chenyizhaophd@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81671125; the Natural Science Foundation of Guangdong Province, No. 2021A1515011115; and Guangzhou Science and Technology Project, No. 202102010346 (all to YZC).

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摘要：

脑出血常伴有由活性氧诱导的氧化应激，后者可导致线粒体功能异常和继发性活性氧的产生，进而造成活性氧积累的恶性循环，导致脑出血的进展。因此，从线粒体开始，抑制恶性循环中活性氧的积累对于减少脑卒中后神经元死亡至关重要。作者所在课题组既往研究发现增加NADPH氧化酶4的表达，可导致神经元凋亡和血脑屏障损伤。此次实验进一步探索NADPH氧化酶4在脑出血神经元中对氧化应激的耐受性、线粒体活性氧以及细胞凋亡以外的神经元死亡模式等恶性循环中的作用。结果发现，腺相关病毒敲低NADPH氧化酶4可有效增强神经元对氧化应激的耐受性，使其更好地抵抗脑出血引起的氧化应激。此外，敲低NADPH氧化酶4还可减少线粒体中活性氧的产生，缓解线粒体损伤，打破继发性活性氧积累导致的恶性循环，减少神经元焦亡，有助于缓解脑出血后继发性脑损伤。最后使用线粒体靶向超氧化物歧化酶模拟物通过来探索活性氧与NADPH氧化酶4之间的关系，发现线粒体靶向超氧化物歧化酶模拟物通可抑制NADPH氧化酶4的表达和神经元细胞焦亡，这与敲低NADPH氧化酶4的效果相似。表明NADPH氧化酶4可能是抑制线粒体中活性氧产生的重要靶点。

https://orcid.org/0000-0003-4765-5699 (Bo-Yun Ding); https://orcid.org/0000-0002-7357-9127 (Yi-Zhao Chen)

关键词: font-family:宋体, ">脑出血, font-family:Calibri, sans-serif, ">NADPHfont-family:宋体, ">氧化酶font-family:Calibri, sans-serif, ">4font-family:宋体, ">, 线粒体活性氧抑制剂, 神经元焦亡, font-family:Calibri, sans-serif, ">caspase 1font-family:宋体, ">, font-family:Calibri, sans-serif, ">caspase4/11font-family:宋体, ">, 消皮素font-family:Calibri, sans-serif, ">Dfont-family:宋体, ">, 神经元耐受性, 活性氧, 继发性脑损伤

Abstract: Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species, which causes abnormal mitochondrial function and secondary reactive oxygen species generation. This creates a vicious cycle leading to reactive oxygen species accumulation, resulting in progression of the pathological process. Therefore, breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage. Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH oxidase 4, NOX4) led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage. The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress, mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage. We found that NOX4 knockdown by adeno-associated virus (AAV-NOX4) in rats enhanced neuronal tolerance to oxidative stress, enabling them to better resist the oxidative stress caused by intracerebral hemorrhage. Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria, relieved mitochondrial damage, prevented secondary reactive oxygen species accumulation, reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats. Finally, we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4. The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis, which is similar to the effect of AAV-NOX4. This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production, and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage.

Key words: caspase 1, caspase4/11, gasdermin D, intracerebral hemorrhage, mitochondria reactive oxygen species inhibitor, NADPH oxidase 4, neuronal pyroptosis, neuronal tolerance, reactive oxygen species, secondary brain injury