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 (7): 1512-1520.doi: 10.4103/1673-5374.355766

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

CDGSH含铁硫结构域蛋白2过表达可减轻脑缺血再灌注损伤

  

  • 出版日期:2023-07-15 发布日期:2023-01-12
  • 基金资助:
    国家自然科学基金项目（81402930）；安徽省高校自然科学基金项目（KJ2021A0688）；国家大学生创新创业计划项目（202110367071）；蚌埠医学院科技项目重点项目（2020byzd017）；蚌埠医学院512人才培养计划项目（BY51201104）

Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury

Miao Hu1, #, Jie Huang1, #, Lei Chen1, Xiao-Rong Sun1, Zi-Meng Yao1, Xu-Hui Tong1, Wen-Jing Jin1, Yu-Xin Zhang1, Shu-Ying Dong1, 2, 3, *   

  1. 1Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China; 2Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, Anhui Province, China; 3Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, Anhui Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Shu-Ying Dong, MD, bbmcdsy@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81402930; Natural Science Foundation of Universities in Anhui Province, No. KJ2021A0688; National College Students Innovation and Entrepreneurship Program, No. 202110367071; Key projects of science and technology projects of Bengbu Medical College, No. 2020byzd017; 512 Talents Training Program of Bengbu Medical College, No. BY51201104 (all to SYD).

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摘要：

铁死亡与脑缺血再灌注损伤有关，而CDGSH含铁硫结构域蛋白2（CISD2）可在头颈癌中抑制铁死亡，因此推测CISD2可能参与脑缺血再灌注损伤。为验证这一假设，实验构建了大脑中动脉闭塞小鼠模型和氧糖剥夺复氧HT22细胞模型，以在体内外模拟脑缺血再灌注损伤，结果发现损伤后小鼠脑组织和细胞中CISD2的表达均明显降低。继而以腺相关病毒转染过表达损伤后小鼠脑组织和细胞中CISD2的表达，可见小鼠神经功能明显改善，脑梗死体积缩小，且HT22细胞存活率下降，细胞损伤减轻，铁死亡相关蛋白谷胱甘肽过氧化物酶4和xCT的表达以及谷胱甘肽含量增加，而丙二醛和铁离子含量以及铁蛋白受体1表达下降，Nrf2的核转位和血红素加氧酶1的表达增加。而以Nrf2抑制剂ML385抑制过表达CISD2的氧糖剥夺复氧HT22细胞，可抑制CISD2过表达的保护作用及Nrf2/血红素加氧酶1通路的活化。过表达CISD2减轻了脑缺血再灌注损伤，为脑缺血再灌注损伤的治疗靶点提供了细胞学和实验动物学的理论支持。

https://orcid.org/0000-0002-1722-7047 (Shu-Ying Dong)

关键词: CISD2, 铁死亡, 脑缺血再灌注损伤, 谷胱甘肽过氧化物酶4, NRF2, 血红素加氧酶1, 铁蛋白受体1, 脑卒中, HT22细胞, 氧糖剥夺复氧损伤

Abstract: CDGSH iron sulfur domain 2 can inhibit ferroptosis, which has been associated with cerebral ischemia/reperfusion, in individuals with head and neck cancer. Therefore, CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury. To validate this hypothesis in the present study, we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro, respectively. We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells. When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately, mouse neurological dysfunction was greatly improved; the cerebral infarct volume was reduced; the survival rate of HT22 cells was increased; HT22 cell injury was alleviated; the expression of ferroptosis-related glutathione peroxidase 4, cystine-glutamate antiporter, and glutathione was increased; the levels of malondialdehyde, iron ions, and the expression of transferrin receptor 1 were decreased; and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased. Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway. Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury, thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

Key words: cerebral ischemia/reperfusion injury, CDGSH iron sulfur domain 2, ferroptosis, glutathione peroxidase 4, heme oxygenase 1, HT22, nuclear-factor E2-related factor 2, oxygen-glucose deprivation/reoxygenation injury, stroke, transferrin receptor 1