The ROS-Mitophagy Signalling Pathway regulates liver endothelial cell survival during ischaemia-reperfusion injury

Research output: Contribution to journalArticlepeer-review

Authors

External organisations

  • University Medical Centre Groningen, University of Groningen, The Netherlands
  • Centre for Liver Research, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, UK.
  • NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
  • Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. d.h.adams@bham.ac.uk.

Abstract

Background: Ischaemia-reperfusion injury (IRI) is the main cause of complications following liver transplantation. Reactive oxygen species (ROS) were thought to be the main regulators of IRI. However recent studies demonstrate that ROS activates the cytoprotective mechanism of autophagy promoting cell survival. Liver IRI initially damages the liver endothelial cells (LEC) but whether ROS-autophagy promotes cell survival in LEC during IRI is not known.

Methods: Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI.

Results: During IRI ROS specifically activate ATG7 promoting autophagic flux and the formation of LC3B positive puncta around mitochondria in primary human LEC.Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition siRNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death.

Conclusion: These findings demonstrate that during liver IRI ROS-dependent
autophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.

Bibliographic note

From: Otto Schuck Date: 5 June 2018 at 00:17:46 BST To: balsin@hotmail.com Subject: Early Accept - Manuscript ID LT-17-755.R2 Reply-To: Livertransplantation@aasld.org 04-Jun-2018 Dr. Ricky Bhogal Dr. Bhogal, Ricky Wolfson Drive Birmingham B15 2TT Birmingham West Midlands United Kingdom of Great Britain and Northern Ireland B15 2TT LT-17-755.R2 The ROS-Mitophagy Signalling Pathway Regulates Liver Endothelial Cell Survival during Ischaemia-Reperfusion Injury

Details

Original languageEnglish
JournalLiver Transplantation
Early online date24 Jul 2018
Publication statusE-pub ahead of print - 24 Jul 2018

Keywords

  • Autophagy, Free radicals, Ischaemic liver injury, Necrosis