Dataset Information

Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.

ABSTRACT: As life expectancy increases, there are greater numbers of patients with liver diseases who 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.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 multi-photon microscopy of isolated hepatocytes and livers from anesthetized mice, respectively.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. Coimmunoprecipitation analysis of hepatocytes and Atg3-knockout cells showed an interaction between Beclin-1 and Atg3, a protein required for autophagosome formation. Intravital multi-photon imaging revealed that overexpression of Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in livers of older mice after I/R.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.

SUBMITTER: Wang JH

PROVIDER: S-EPMC3221865 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.

Wang Jin-Hee JH Ahn In-Sook IS Fischer Trevan D TD Byeon Jae-Il JI Dunn William A WA Behrns Kevin E KE Leeuwenburgh Christiaan C Kim Jae-Sung JS

Gastroenterology 20110818 6

<h4>Background & aims</h4>As life expectancy increases, there are greater numbers of patients with liver diseases who 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.<h4>Methods</h4>Hepatocytes and liver ...[more]

PMID: 21854730

Similar Datasets

Project description:Experimental Design: 1. The goal of the experiment: Age-Dependent Gene Expression Profiles After Hepatic Ischemia/Reperfusion: Implications for the AP-1 and Ubiquitin-Proteosome Pathways 2. Brief description of the experiment: Hepatic ischemia/reperfusion (I/R) injury is a complication of liver surgery, transplantation and shock. Our previous studies have suggested there is an age-dependent response to I/R. In the present study, we examined global gene expression after liver I/R in young (4-5 weeks) and adult (12-14 months) mice using Affymetrix microarray. Gene expression was filtered based on a change in expression of 1.5-fold relative to respective controls and then analyzed by ANOVA. Seventy-two genes in young mice and 56 genes in adult mice had significantly increased expression. Of these, only 18 were up-regulated in both age groups. In young mice, 289 genes were down-regulated whereas in adult mice, 874 genes were decreased. Of these genes, 175 genes were decreased in both groups. Pathway and network analyses of up- and down-regulated gene lists revealed a number of notable differences between young and adult mice. Of these, we found that genes related to the activating protein-1 (AP-1) pathway were upregulated preferentially in young mice. This corresponded with an increase in AP-1 activation in young versus adult mice. Finally, we found that genes related to the ubiquitin-proteasome pathway were selectively down-regulated in adult mice. This was accompanied by reduced degradation of the inhibitory protein, I?B?, in adult mice. The data demonstrate specific, pathway- and network-related differences in gene expression profiles between young and adult mice in the response to I/R. More specifically, we have identified two pathways that may contribute to the superior response to I/R in young mice which represent potential therapeutic targets. Keywords: treated vs non treated 2 age groups of 6 young and 6 adult mice that underwent either 90 minutes of partial ischemia followed by 1 hour of reperfusion (n=3) or sham operation (n=3) We used microarray to uncover the genomic response after ischemia reperfusion in 2 different age groups

Dataset Information

Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.

Publications

Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure