Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage

被引：196
作者：
Zhang, Zhuwei [1 ,2 ]
Wu, Yu [1 ,2 ]
Yuan, Shuai [1 ,2 ]
Zhang, Peng [1 ,2 ]
Zhang, Juyi [1 ,2 ]
Li, Haiying [1 ,2 ]
Li, Xiang [1 ,2 ]
Shen, Haitao [1 ,2 ]
Wang, Zhong [1 ,2 ]
Chen, Gang [1 ,2 ]
机构：
[1] Soochow Univ, Affiliated Hosp 1, Dept Neurosurg, 188 Shizi St, Suzhou 215006, Jiangsu, Peoples R China
[2] Soochow Univ, Affiliated Hosp 1, Brain & Nerve Res Lab, Suzhou, Jiangsu, Peoples R China
来源：
BRAIN RESEARCH | 2018年 / 1701卷
基金：
中国国家自然科学基金;
关键词：
Glutathione peroxidase 4; Reactive oxygen species; Ferroptosis; Secondary brain injury; Intracerebral hemorrhage; OXYGEN SPECIES ROS; CELL-DEATH; SUBARACHNOID HEMORRHAGE; INFLAMMATION; MECHANISMS; RECEPTOR;
D O I：
10.1016/j.brainres.2018.09.012
中图分类号：
Q189 [神经科学];
学科分类号：
071006 ;
摘要：
Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH.
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收藏
页码：112 / 125
页数：14
相关论文
共 40 条
[1]   Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain [J].
Bellinger, Frederick P. ;
Bellinger, Miyoko T. ;
Seale, Lucia A. ;
Takemoto, Andrea S. ;
Raman, Arjun V. ;
Miki, Takanori ;
Manning-Bog, Amy B. ;
Berry, Marla J. ;
White, Lon R. ;
Ross, G. Webster .
MOLECULAR NEURODEGENERATION, 2011, 6
[2]   Glutathione peroxidase 4: a new player in neurodegeneration? [J].
Cardoso, B. R. ;
Hare, D. J. ;
Bush, A. I. ;
Roberts, B. R. .
MOLECULAR PSYCHIATRY, 2017, 22 (03) :328-335
[3]   Glutathione peroxidase 4 has a major role in protecting mitochondria from oxidative damage and maintaining oxidative phosphorylation complexes in gut epithelial cells [J].
Cole-Ezea, Patience ;
Swan, Dan ;
Shanley, Daryl ;
Hesketh, John .
FREE RADICAL BIOLOGY AND MEDICINE, 2012, 53 (03) :488-497
[4]   Regulated necrosis: disease relevance and therapeutic opportunities [J].
Conrad, Marcus ;
Angeli, Jose Pedro Friedmann ;
Vandenabeele, Peter ;
Stockwell, Brent R. .
NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (05) :348-366
[5]   Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].
Dixon, Scott J. ;
Lemberg, Kathryn M. ;
Lamprecht, Michael R. ;
Skouta, Rachid ;
Zaitsev, Eleina M. ;
Gleason, Caroline E. ;
Patel, Darpan N. ;
Bauer, Andras J. ;
Cantley, Alexandra M. ;
Yang, Wan Seok ;
Morrison, Barclay, III ;
Stockwell, Brent R. .
CELL, 2012, 149 (05) :1060-1072
[6]   Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells [J].
Dolma, S ;
Lessnick, SL ;
Hahn, WC ;
Stockwell, BR .
CANCER CELL, 2003, 3 (03) :285-296
[7]   Tumor necrosis factor receptor-associated factor 6 participates in early brain injury after subarachnoid hemorrhage in rats through inhibiting autophagy and promoting oxidative stress [J].
Dou, Yang ;
Shen, Haitao ;
Feng, Dongxia ;
Li, Haiying ;
Tian, Xiaodi ;
Zhang, Jian ;
Wang, Zhong ;
Chen, Gang .
JOURNAL OF NEUROCHEMISTRY, 2017, 142 (03) :478-492
[8]   Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy [J].
Duan, Xiaochun ;
Wen, Zunjia ;
Shen, Haitao ;
Shen, Meifen ;
Chen, Gang .
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2016, 2016
[9]   Angiotensin II modulates BBB permeability via activation of the AT1 receptor in brain endothelial cells [J].
Fleegal-DeMotta, Melissa A. ;
Doghu, Shinya ;
Banks, William A. .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2009, 29 (03) :640-647
[10]   Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 [J].
Galluzzi, L. ;
Bravo-San Pedro, J. M. ;
Vitale, I. ;
Aaronson, S. A. ;
Abrams, J. M. ;
Adam, D. ;
Alnemri, E. S. ;
Altucci, L. ;
Andrews, D. ;
Annicchiarico-Petruzzelli, M. ;
Baehrecke, E. H. ;
Bazan, N. G. ;
Bertrand, M. J. ;
Bianchi, K. ;
Blagosklonny, M. V. ;
Blomgren, K. ;
Borner, C. ;
Bredesen, D. E. ;
Brenner, C. ;
Campanella, M. ;
Candi, E. ;
Cecconi, F. ;
Chan, F. K. ;
Chandel, N. S. ;
Cheng, E. H. ;
Chipuk, J. E. ;
Cidlowski, J. A. ;
Ciechanover, A. ;
Dawson, T. M. ;
Dawson, V. L. ;
De laurenzi, V. ;
De Maria, R. ;
Debatin, K-M ;
Di Daniele, N. ;
Dixit, V. M. ;
Dynlacht, B. D. ;
El-Deiry, W. S. ;
Fimia, G. M. ;
Flavell, R. A. ;
Fulda, S. ;
Garrido, C. ;
Gougeon, M-L ;
Green, D. R. ;
Gronemeyer, H. ;
Hajnoczky, G. ;
Hardwick, J. M. ;
Hengartner, M. O. ;
Ichijo, H. ;
Joseph, B. ;
Jost, P. J. .
CELL DEATH AND DIFFERENTIATION, 2015, 22 (01) :58-73
1234