缺氧(环境)
细胞生物学
血脑屏障
程序性细胞死亡
谷胱甘肽
活性氧
内皮干细胞
体内
斑马鱼
生物
GPX4
化学
体外
生物化学
谷胱甘肽过氧化物酶
细胞凋亡
神经科学
中枢神经系统
氧气
生物技术
有机化学
基因
酶
作者
Qiuling Liu,Tujing Song,Bing Chen,Jingjing Zhang,Li Wen
标识
DOI:10.1096/fj.202201765r
摘要
Abstract Hypoxia is pivotal to the pathogeneses of myriad disorders, especially hypoxic cerebropathy. Much is known about the damage to the blood–brain barrier (BBB) in response to hypoxia. Studies have shown that endothelial cell death is closely linked to functional impairment of BBB. Mounting evidences have demonstrated that ferroptosis, a new pathway regulating cell death, is implicated in brain injury. However, whether ferroptosis is involved in hypoxia‐induced BBB disruption remains ambiguous. Here, we utilized in vivo zebrafish and in vitro bEnd.3 cells to explore the correlation between endothelial ferroptosis and hypoxia‐induced BBB damage. We found that hypoxic treatment for 45 min can induce BBB disruption by triggering down‐regulation of claudin‐5 (CLDN5) both in zebrafish cerebrovascluar endothelial cells and bEnd.3 cells. Besides, in vitro and in vivo studies revealed the cysteine/glutamate antiporter xCT (also known as solute carrier family 7 member 11; SLC7A11) decrease, glutathione peroxidase 4 (GPX4) and glutathione (GSH) reduction, 4‐Hydroxynonenal (4‐HNE) increasement, malondialdehyde (MDA) upregulation and reactive oxygen species (ROS) accumulation in hypoxia group. Further mechanism studies indicated that hypoxia‐induced BBB damage might associate with microvascular endothelial cellular ferroptosis, since hypoxic exposure significantly activated the expression of ferroptosis‐related genes ( Ptgs2 , Por , Lpcat3 , Alox5 , Alox12 , Nfe2l2, and Ncoa4 ) and inhibited the expression of Slc7a11 . Additionally, the application of 20 μM ferrostatin‐1 (Fer‐1), a ferroptosis inhibitor, could partially alleviate BBB disruption under hypoxia, suggesting that inhibition of ferroptosis might be a potential strategy for some neurological diseases with BBB defect.
科研通智能强力驱动
Strongly Powered by AbleSci AI