Basic Research Paper
The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice
Volume 8, Issue 6
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Pages 954 - 962http://dx.doi.org/10.4161/auto.19927
: autophagy, hydrogen sulphide, ischemia-reperfusion injury, liver, mouse
Authors: Dawei Wang, Yong Ma, Zhengtian Li, Kai Kang, Xueying Sun, Shangha Pan, Jizhou Wang, Huayang Pan, Lianxin Liu, Desen Liang and Hongchi Jiang View affiliations
Hydrogen sulphide (H2S) exerts a protective effect in hepatic ischemia-reperfusion (I/R) injury. However, the exact mechanism of H2S action remains largely unknown. This study was designed to investigate the role of the PtdIns3K-AKT1 pathways and autophagy in the protective effect of H2S against hepatic I/R injury. Primary cultured mouse hepatocytes and livers with or without NaHS (a donor of H2S) preconditioning were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. In certain groups, they were also pretreated with LY294002 (AKT1-specific inhibitor), 3-methyladenine (3MA, autophagy inhibitor) or rapamycin (autophagy enhancer), alone or simultaneously. Cell viability, expression of P-AKT1, T-AKT1, LC3 and BECN1 were examined. The severity of liver injury was measured by the levels of serum aminotransferase and inflammatory cytokine, apoptosis and histological examination. GFP-LC3 redistribution and transmission electron microscopy were used to test the activity of autophagy. H2S preconditioning activated PtdIns3K-AKT1 signaling in hepatocytes. LY294002 could abolish the AKT1 activation and attenuate the protective effect of H2S on hepatocytes A/R and hepatic I/R injuries. H2S suppressed hepatic autophagy in vitro and in vivo. Further reducing autophagy by 3MA also diminished the protective effect of H2S, while rapamycin could reverse the autophagy inhibitory effect and enhance the protective effect of H2S against hepatocytes A/R and hepatic I/R injuries, consequently. Taken together, H2S protects against hepatocytic A/R and hepatic I/R injuries, at least in part, through AKT1 activation but not autophagy. An autophagy agonist could be applied to potentiate this hepatoprotective effect by reversing the autophagy inhibition of H2S.
Received: November 6, 2011; Accepted: March 6, 2012; Published Online: June 1, 2012
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