Inhibition of hypoxia-inducible factor-1α alleviates acinar cell necrosis in a mouse model of acute pancreatitis

Qinhao Shen; Xiaolei Shi; Lide Tao; Qingtian Zhu; Weiming Xiao; Yanbing Ding; Weijuan Gong; Guotao Lu; Mei Wang; Guanghuai Yao

doi:10.1016/j.bbrc.2021.07.043

Inhibition of hypoxia-inducible factor-1α alleviates acinar cell necrosis in a mouse model of acute pancreatitis

Biochem Biophys Res Commun. 2021 Oct 1:572:72-79. doi: 10.1016/j.bbrc.2021.07.043. Epub 2021 Aug 3.

Authors

Qinhao Shen¹, Xiaolei Shi¹, Lide Tao², Qingtian Zhu¹, Weiming Xiao¹, Yanbing Ding¹, Weijuan Gong¹, Guotao Lu³, Mei Wang⁴, Guanghuai Yao⁵

Affiliations

¹ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
² Department of Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
³ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China. Electronic address: gtlu@yzu.edu.cn.
⁴ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China. Electronic address: wangmei@yzu.edu.cn.
⁵ Pancreatic Center, Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China. Electronic address: ghyao@yzu.edu.cn.

PMID: 34358966
DOI: 10.1016/j.bbrc.2021.07.043

Abstract

Hypoxia-inducible factor-1α (Hif1α) is activated in hypoxia and is closely related to oxidative stress, immunity and cell metabolism. Recently, it is reported that Hif1α is involved in atherosclerosis, ischemia-reperfusion (I/R) injury, alcoholic liver disease and pancreatic tumors. In this study, we found that Hif1 signal pathway is significantly changed in pancreas of acute pancreatitis (AP) mice. Meanwhile, we verified that the high expression of Hif1α injured pancreatic tissues of cerulean-induced AP mice, which prompting that Hif1α participated in the progress of histopathology on AP. We applied a Hif1α inhibitor PX478 and observed that it could alleviate histological injury of pancreas as well as the levels of serum amylase, lipase and proinflammatory cytokine in the murine model of AP induced by caerulein. In addition, PX478 could reduce the formation of necrosome (RIP3 and p-MLKL) and the generation of reactive oxygen species (ROS) in AP mice. Correspondingly, we further confirmed the effectiveness of PX478 in vitro and found that inhibiting Hif1α could mitigated the necrosis of pancreatic acinar cells via reducing the RIP3 and p-MLKL expression and the ROS production. In conclusion, inhibiting Hif1α could protect against acinar cells necrosis in AP, which may provide a new target for the prevention and treatment of AP clinically.

Keywords: Acinar cell; Acute pancreatitis; Hif1α; Necroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acinar Cells / drug effects*
Acinar Cells / metabolism
Animals
Disease Models, Animal*
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Mice
Mice, Inbred ICR
Mustard Compounds / pharmacology*
Necrosis / drug therapy*
Necrosis / metabolism
Pancreatitis / drug therapy*
Pancreatitis / metabolism
Phenylpropionates / pharmacology*

Substances

2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
Hypoxia-Inducible Factor 1, alpha Subunit
Mustard Compounds
Phenylpropionates