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Original Research

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Chac1 silencing mitigates hemorrhagic shock-induced intestinal injury by inhibiting oxidative stress and ferroptosis

  • Hao Yao1,†
  • Yan Wang1,†
  • Wuming Zhou1
  • Ce Xu1
  • Xin Ge1,2,*,
  • Jiandong Zhu3,*,

1Department of Critical Care Medicine, Wuxi 9th People’s Hospital Affiliated to Soochow University, 214000 Wuxi, Jiangsu, China

2Orthopedic Institution of Wuxi City, 214000 Wuxi, Jiangsu, China

3Department of Gastroenterology, Wuxi 9th People’s Hospital Affiliated to Soochow University, 214000 Wuxi, Jiangsu, China

DOI: 10.22514/sv.2023.113 Vol.19,Issue 6,November 2023 pp.184-193

Submitted: 16 September 2023 Accepted: 26 October 2023

Published: 08 November 2023

*Corresponding Author(s): Xin Ge E-mail: gexin2021@suda.edu.cn

† These authors contributed equally.

Abstract

Hemorrhagic shock (HS) is a common and significant cause of mortality and morbidity, often resulting in structural damage and dysfunction of the intestines. ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (Chac1) has been reported to be involved in the regulation of oxidative stress and ferroptosis in mammals. Herein, we investigate the effects of Chac1 on HS-induced intestinal injury induced by HS both in vitro and in vivo. Sprague-Dawley rat model with HS was established, and our investigations showed upregulation of the mRNA and protein levels of Chac1 in the model’s ileum tissues. Histopathological analysis revealed that knockdown of Chac1 attenuated the intestinal injury induced by HS. Depletion of Chac1 also reduced the increase in intestinal fatty acid binding protein (I-FABP) concentration. Immunofluorescence staining indicated that silencing Chac1 significantly suppressed the downregulation of occludin and zonula occludens-1 (ZO-1). HS-induced changes in lipid peroxidation (LPO), malondialdehyde (MDA), and glutathione (GSH) levels were reversed in the absence of Chac1, suggesting that downregulation of Chac1 alleviated HS-induced oxidative stress. Additionally, HS led to a decrease in glutathione peroxidase 4 (Gpx4) and ferritin heavy chain 1 (Fth1) expression, along with an increase in ferrous ion (Fe2+) concentration. Knockdown of Chac1 significantly inhibited ferroptosis by increasing Gpx4 and Fth1 expression while reducing the Fe2+ concentration. In vitro experiments using the rat small intestine crypt epithelial cells (IEC-6) demonstrated that depletion of Chac1 suppressed oxidative stress and ferroptosis induced by hypoxia/reoxygenation (H/R). In conclusion, our study provides evidence that downregulation of Chac1 mitigates HS-induced intestinal injury by inhibiting oxidative stress and ferroptosis.


Keywords

Chac1; Hemorrhagic shock; Intestinal injury; Oxidative stress; Ferroptosis


Cite and Share

Hao Yao,Yan Wang,Wuming Zhou,Ce Xu,Xin Ge,Jiandong Zhu. Chac1 silencing mitigates hemorrhagic shock-induced intestinal injury by inhibiting oxidative stress and ferroptosis. Signa Vitae. 2023. 19(6);184-193.

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