Abstract
BackgroundGrowing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy.MethodsRIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro.ResultsIn liver IR, the expression of LC3-II peaked 12–24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA.ConclusionsRIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.
Highlights
Liver ischemia/reperfusion (IR) injury (IRI) is a phenomenon in which cellular damage caused by hypoxia is accentuated following return of blood flow and restoration of oxygen delivery
Autophagy was induced in mouse liver ischemia reperfusion injury
Heme oxygenase-1 (HO-1) and light chain 3-II (LC3-II) expression was induced in the remote ischemic preconditioning (RIPC)+IR group, but when heme oxygenase (HO)-1 expression was inhibited by Znpp in the Znpp+RIPC+IR group, we saw no increase in HO-1 expression by RIPC following induction of LC3-II expression
Summary
Liver ischemia/reperfusion (IR) injury (IRI) is a phenomenon in which cellular damage caused by hypoxia is accentuated following return of blood flow and restoration of oxygen delivery. This remains an important clinical problem during shock, hepatic resection, and liver transplantation. The first work on remote ischemic preconditioning (RIPC), described by Przyklenk, et al in 1993, showed that brief occlusion of the circumflex artery protects myocardium from subsequent continuous IRI. This proved to be a novel and simple way to protect the liver without direct stress [3]. The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy
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