Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 68, Issue -, Pages 168-177Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.12.014
Keywords
Autophagy; Calpains; Carbon monoxide; Heme oxygenase-1; Liver ischemia/reperfusion
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Science, ICT, and Future Planning [2013R1A1A3008145]
- Hong-Ik Cho received a Global Ph.D. Fellowship Program support from the NRF funded by the Ministry of Education, Science, and Technology [2012016419]
Ask authors/readers for more resources
Liver ischemia and reperfusion (1/R) injury is characterized by oxidative stress that is accompanied by alterations of the endogenous defensive system. Emerging evidence suggests a protective role for autophagy induced by multiple stressors including reactive oxygen species. Meanwhile, heme oxygenase-1 (HO-1) has long been implicated in cytoprotection against oxidative stress in vitro and in vivo. Therefore, we investigated the impact of autophagy in the pathogenesis of liver I/R and its molecular mechanisms, particularly its linkage to HO-1. By using transmission electron microscopic analysis and biochemical autophagic flux assays with microtubule-associated protein 1 light chain 3-II, and beclin-1, representative autophagy markers, and p62, a selective substrate for autophagy, we found that reperfusion reduced autophagy both in the rat liver and in primary cultured hepatocytes. When autophagy was further inhibited with chloroquine or wortmannin, I/R-induced hepatocellular injury was aggravated. While livers that underwent I/R showed increased levels of mammalian target of rapamaycin and calpain 1 and 2, inhibition of calpain 1 and 2 induced an autophagic response in hepatocytes subjected to hypoxia/reoxygenation. HO-1 increased autophagy, and HO-1 reduced I/R-induced calcium overload in hepatocytes and prevented calpain 2 activation both in vivo and in vitro. Taken together, these findings suggest that the impaired autophagy during liver I/R, which is mediated by calcium overload and calpain activation, contributes to hepatocellular damage and the HO-1 system protects the liver I/R injury through enhancing autophagy. (c) 2013 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available