Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy.

Autor: Yao X; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: yaoxueya1086@126.com., Liu Y; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: liuyingxiang187@163.com., Sui Y; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: syh11123@sina.com., Zheng M; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: zhengmiao111@126.com., Zhu L; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: medzhuling@126.com., Li Q; Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: quanfuli185@163.com., Irwin MG; Department of Anaesthesiology, University of Hong Kong, China. Electronic address: mgirwin@hku.hk., Yang L; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: lqyang72721@126.com., Zhan Q; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: zhanqionghui328@163.com., Xiao J; Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China. Electronic address: applexiaomz@163.com.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Aug; Vol. 177, pp. 117038. Date of Electronic Publication: 2024 Jul 13.
DOI: 10.1016/j.biopha.2024.117038
Abstrakt: Introduction: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear.
Objectives: This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx.
Methods: In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3β and Flag-tagged GSK3β, α2-ADR antagonist, GSK3β inhibitor, AKT inhibitor were used to identify the role of GSK3β in DEX-mediated autophagic flux and hepatocyte proliferation.
Results: Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3β activity by SB216763 and si-GSK3β enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor.
Conclusion: Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3β activity in an α2-ADR-dependent manner.
Competing Interests: Declaration of Competing Interest All authors have declared no conflict of interest
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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