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Gastroenterology. 2011 Aug 17. [Epub ahead of print]
Autophagy Suppresses Age-Dependent Ischemia and Reperfusion Injury in Livers of Mice.
自噬抑制了肝I/R损伤
Wang JH, Ahn IS, Fischer TD, Byeon JI, Dunn WA Jr, Behrns KE, Leeuwenburgh C, Kim JS.
SourceDepartment of Surgery, University of Florida, Gainesville, FL 32610.
Abstract
BACKGROUND & AIMS: As life expectancy increases, there are greater numbers of patients with liver diseases that require surgery or transplantation. Livers of older patients have significantly less reparative capacity following ischemia and reperfusion (I/R) injury, which occurs during these operations. There are no strategies to reduce the age-dependent I/R injury. We investigated the role of autophagy in the age dependence of sensitivity to I/R injury.
METHODS: Hepatocytes and livers from 3- and 26-month-old mice were subjected to in vitro and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins (Atg). Mitochondrial dysfunction was visualized using confocal and intravital multiphoton microscopy of isolated hepatocytes and livers from anesthetized mice, respectively.
RESULTS: Immunoblot, autophagic flux, genetic, and imaging analyses all associated the increase in sensitivity to I/R injury with age with decreased autophagy and subsequent mitochondrial dysfunction, due to calpain-mediated loss of Atg4B. Overexpression of either Atg4B or Beclin-1 recovered Atg4B, increased autophagy, blocked the onset of the mitochondrial permeability transition, and suppressed cell death after I/R in old hepatocytes. Co-immunoprecipitation analysis of hepatocytes and Atg3-knockout cells demonstrated an interaction between Beclin-1 and Atg3, a protein required for autophagosome formation. Intravital multiphoton imaging revealed that overexpression of Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in livers of older mice after I/R.
CONCLUSION: Loss of Atg4B in livers of old mice increases their sensitivity to I/R injury. Increasing autophagy might ameliorate liver damage and restore mitochondrial function after I/R.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 21854730 [PubMed - as supplied by publisher]
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