1. Academic Validation
  2. Succinate pretreatment attenuates intestinal ischemia-reperfusion injury by inhibiting necroptosis and inflammation via upregulating Klf4

Succinate pretreatment attenuates intestinal ischemia-reperfusion injury by inhibiting necroptosis and inflammation via upregulating Klf4

  • Int Immunopharmacol. 2023 Jun 5;120:110425. doi: 10.1016/j.intimp.2023.110425.
Zhen Cao 1 Silong Mu 1 Maihuan Wang 1 Yun Zhang 1 Guijun Zou 1 Xinpu Yuan 1 Yun Huang 1 Siwang Yu 2 Jinming Zhang 3 Chaojun Zhang 4
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs; Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.
  • 3 Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China. Electronic address: 694760993@qq.com.
  • 4 Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China. Electronic address: zcjdlyxzx@163.com.
Abstract

Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight junction proteins is the initiating factor, which then leads to a large number of bacteria and endotoxins in the intestine into the bloodstream causing stress and distant organ damage. The release of inflammatory mediators and abnormal programmed death of intestinal epithelial cells are important factors of intestinal barrier damage. Succinate is an intermediate product of the tricarboxylic acid cycle with anti-inflammatory and pro-angiogenic activities, but its role in the maintenance of intestinal barrier homeostasis after I/R has not been fully elucidated. In this study, we explored the effect of succinate on intestinal ischemia-reperfusion injury and the possible mechanism of its role by flow cytometry, western blotting, real-time quantitative PCR and immunostaining. The results of pretreatment with succinate in the mouse intestinal I/R model and IEC-6 cells hypoxia-reoxygenation (H/R) model revealed a reduction in tissue damage, Necroptosis and associated inflammation due to ischemia-reperfusion. Furthermore, it was found that the protective effect of succinate pretreatment may be associated with the transcriptional upregulation of the inflammatory protein KLF4 and the protective effect of intestinal barrier of succinate was diminished after inhibition of KLF4. Thus, our results suggest that succinate can exert a protective effect in intestinal ischemia-reperfusion injury through upregulation of KLF4 and also demonstrate the potential therapeutic value of succinate pretreatment in acute I/R injury of the intestine.

Keywords

Inflammation; Intestine; Ischemia reperfusion; Necroptosis; Succinate.

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