Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy

Yun Wang; Jian Shen; Xuanxuan Xiong; Yonghua Xu; Hai Zhang; Changjun Huang; Yuan Tian; Chengyu Jiao; Xuehao Wang; Xiangcheng Li

doi:10.1371/journal.pone.0098834

Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy

PLoS One. 2014 Jun 10;9(6):e98834. doi: 10.1371/journal.pone.0098834. eCollection 2014.

Authors

Yun Wang¹, Jian Shen², Xuanxuan Xiong³, Yonghua Xu⁴, Hai Zhang⁵, Changjun Huang⁶, Yuan Tian⁶, Chengyu Jiao⁶, Xuehao Wang⁶, Xiangcheng Li⁶

Affiliations

¹ Department of Oncological Surgery 2, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xuzhou), The Tumor Research Institute of the Southeast University (Xuzhou), Xuzhou, Jiangsu Province, China.
² Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
³ Department of Gastroenterology II, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xuzhou), Xuzhou, Jiangsu Province, China.
⁴ Department of General Surgery, Yancheng First People's Hospital, Yancheng, Jiangsu Province, China.
⁵ Department of General Surgery, The First Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China.
⁶ Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.

Abstract

Background: Growing 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.

Methods: RIPC 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.

Results: In 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.

Conclusions: RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy* / drug effects
Autophagy* / genetics
Cell Line
Enzyme Activation
Gene Expression
Heme Oxygenase-1 / antagonists & inhibitors
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism*
Ischemic Preconditioning*
Liver / blood supply*
Liver / metabolism*
Liver / pathology
Liver Diseases / genetics
Liver Diseases / metabolism*
Liver Diseases / pathology
Male
Mice
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Protoporphyrins / pharmacology
RNA Interference
RNA, Small Interfering / genetics
Reperfusion Injury / genetics
Reperfusion Injury / metabolism*
Signal Transduction / drug effects
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Protoporphyrins
RNA, Small Interfering
zinc protoporphyrin
Heme Oxygenase-1
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases

Grants and funding

The study was supported by grants from the National Natural Science Foundation of China (81170415) from Dr. Xiangcheng Li, and from the National Natural Science Foundation of China (81302108) from Dr. Jian Shen, and from Nanjing Medical University (2012NJMU087). Dr. Xiangcheng Li had a role in study design, data collection and analysis, decision to publish, and Dr. Jian Shen also had role in study design, data collection and analysis, decision to publish.