Work

Ferroptosis of brain microvascular endothelial cells contributes to hypoxia‐induced blood–brain barrier injury

Year: 2023

Type: article

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.

Source: The FASEB Journal

DOI: 10.1096/fj.202201765r

Authors: Qiuling Liu, Tujing Song, Bing Chen, Jingjing Zhang, Wen Li

Institutions: Guangdong Medical College, Affiliated Hospital of Guangdong Medical College Hospital

Language: English

Topic: Barrier Structure and Function Studies

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,390