Weizhe Zhong1,2,3, Xiaowei Wang1,2,3, Zhuqing Rao4, Xiongxiong Pan4, Yu Sun1,2,3, Tao Jiang1,2,3,5, Ping Wang1,2,3, Haoming Zhou1,2,3, Xuehao Wang1,2,3. 1. Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. 2. Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. 3. Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. 4. Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. 5. Department of Surgical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Abstract
BACKGROUND: Aggravated liver ischemia and reperfusion (IR) injury has been reported in aged mice. Although necroptosis inhibition showed no crucial effect on hepatic IR injury in young mice, whether and how necroptosis affects liver IR injury in aged mice remains unclear. METHODS: Young and aged mice were subjected to liver IR modeling. Liver injury, hepatocyte necroptosis and endoplasmic reticulum (ER) stress were analyzed in different groups. RESULTS: Significantly increased liver necroptosis was found in aged mice post IR compared with young mice. Necroptosis inhibition by necrostatin-1 (Nec-1) decreased hepatocyte necroptosis and liver injury post IR in aged mice, with no significant effects on young mice. Furthermore, IR induced ER stress in both young and aged mice, and enhanced ER stress was observed in aged mice post IR. Administration of 4-phenylbutyrate (4-PBA), an ER stress antagonist, alleviated liver IR injury in both young and aged mice. However, ER stress inhibition reduced hepatocyte necroptosis in aged mice but not in young mice. CONCLUSIONS: Aging increased ER stress in IR-stressed hepatocytes, leading to aggravated necroptosis and liver IR injury. Our study demonstrated a novel mechanism of ER stress in the regulation of hepatocyte necroptosis in aged livers post IR, which would be a potential therapeutic target to reduce liver IR injury in elderly patients. 2020 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Aggravated liver ischemia and reperfusion (IR) injury has been reported in aged mice. Although necroptosis inhibition showed no crucial effect on hepatic IR injury in young mice, whether and how necroptosis affects liver IR injury in aged mice remains unclear. METHODS: Young and aged mice were subjected to liver IR modeling. Liver injury, hepatocyte necroptosis and endoplasmic reticulum (ER) stress were analyzed in different groups. RESULTS: Significantly increased liver necroptosis was found in aged mice post IR compared with young mice. Necroptosis inhibition by necrostatin-1 (Nec-1) decreased hepatocyte necroptosis and liver injury post IR in aged mice, with no significant effects on young mice. Furthermore, IR induced ER stress in both young and aged mice, and enhanced ER stress was observed in aged mice post IR. Administration of 4-phenylbutyrate (4-PBA), an ER stress antagonist, alleviated liver IR injury in both young and aged mice. However, ER stress inhibition reduced hepatocyte necroptosis in aged mice but not in young mice. CONCLUSIONS: Aging increased ER stress in IR-stressed hepatocytes, leading to aggravated necroptosis and liver IR injury. Our study demonstrated a novel mechanism of ER stress in the regulation of hepatocyte necroptosis in aged livers post IR, which would be a potential therapeutic target to reduce liver IR injury in elderly patients. 2020 Annals of Translational Medicine. All rights reserved.
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