Role of microglial HIF-3α in cognitive impairment after hemorrhagic shock and resuscitation and the relationship with neuronal ferroptosis in mice
10.3760/cma.j.cn131073-20240514-00217
- VernacularTitle:小胶质细胞HIF-3α在小鼠失血性休克复苏后认知功能障碍中的作用及其与神经元铁死亡的关系
- Author:
Aoxue XU
1
;
Song XUE
1
;
Xianwen HU
1
;
Chunxia HUANG
1
Author Information
1. 安徽医科大学第二附属医院麻醉与围术期医学科，合肥 230601
- Publication Type:Journal Article
- Keywords:
Basic helix-loop-helix transcription factors;
Microglial cell;
Shock, hemorrhagic;
Resuscitation;
Cognition disorders;
Ferroptosis;
Neurons
- From:
Chinese Journal of Anesthesiology
2025;45(2):214-220
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To evaluate the role of microglial hypoxia-inducible factor-3α (HIF-3α) in cognitive impairment after hemorrhagic shock and resuscitation(HSR) and the relationship with neuronal ferroptosis in mice.Methods:Twenty-four specific pathogen-free healthy male C57BL/6 mice, aged 10 weeks, weighing 25-30 g, were divided into 3 groups ( n=8 each) using a random number table method: sham operation group (Sham group), HSR group, and HSR+ ferroptosis inhibitor (ferrostatin-1) group (HSR+ Fer-1 group). Sixteen C57BL/6 mice and 16 HIF-3α flox/flox: Cx3crl Cre (HIF-3α CKO) mice were selected and assigned to 2 groups ( n=8 each) using a random number table method: sham operation group (WT-Sham group, HIF-3α CKO-Sham group) and HSR group (WT-HSR group, HIF-3α CKO-HSR group). To establish the HSR model, 40% of the total blood volume was withdrawn at a steady rate via the right carotid artery within 30 min and 1 h later reinfused through the jugular vein over a period of 30 min. Ferrostatin-1 10 mg/kg was nasally administered once mice recovered after HSR in HSR+ Fer-1 group. The cognitive function was evaluated by the novel object recognition test at 72 h after developing the model. The hippocampal tissues were collected under deep anesthesia after evaluation for determination of the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) in the ipsilateral hippocampi (by Western blot) and expression of microglial HIF-3α and GPX4 and FTH1 in neurons in the hippocampal CA3 region (by immunofluorescence staining) and for examination of the ultrastructure of mitochondria in hippocampal neurons (with a transmission electron microscope). Results:Compared to Sham group, the cognitive and discrimination indexes were significantly decreased, and the expression of GPX4 and FTH1 was down-regulated in HSR group ( P<0.05). Compared to HSR group, the cognitive and discrimination indexes were significantly increased, and the expression of GPX4 and FTH1 in the hippocampi was up-regulated in HSR+ Fer-1 group ( P<0.05). Compared to WT-Sham group, the cognitive and discrimination indexes were significantly decreased, and the expression of microglial HIF-3α in the hippocampal CA3 region was up-regulated, and the expression of neuronal GPX4 and FTH1 was down-regulated in WT-HSR group ( P<0.05), and no statistically significant change was found in the aforementioned parameters in HIF-3α CKO-Sham group ( P>0.05). Compared to WT-HSR group, the cognitive and discrimination indexes were significantly increased, and the expression of microglial HIF-3α in the hippocampal CA3 region was down-regulated, the expression of GPX4 and FTH1 was up-regulated ( P<0.05), and mitochondrial damage in the neurons was significantly attenuated in HIF-3α CKO-HSR group. Conclusions:Microglial HIF-3α-mediated ferroptosis in hippocampal neurons is involved in cognitive impairment following HSR in mice.
