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Changes of ferroptosis related pathways in hippocampus of mice exposed to high-altitude hypoxia

CHANG Xi-Wen^1,2, ZHAO An-Peng^1,2, ZHONG Yan², LIU Fei-Fei², WANG Rong^2,*

¹School of Pharmacy, Lanzhou University, Lanzhou 730000, China；²Department of Pharmacy, The 940th Hospital of PLA Joint Logistics Support Force, Lanzhou 730050, China

Abstract

The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2’s anti-lipid peroxidation effect, ultimately leading to ferroptosis.

Key words: high-altitude hypoxia; ferroptosis; glutathione metabolism; iron metabolism; lipid peroxidation

Received: 　　Accepted:

Corresponding author: 王荣　　E-mail:

DOI: 10.13294/j.aps.2024.0057

Citing This Article：

CHANG Xi-Wen, ZHAO An-Peng, ZHONG Yan, LIU Fei-Fei, WANG Rong. Changes of ferroptosis related pathways in hippocampus of mice exposed to high-altitude hypoxia. Acta Physiol Sin 2024; 76 (4): 507-516 (in Chinese with English abstract).