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

Ricky Bhogal; Christopher Weston; Susanne Velduis; Leuvenink Henri GD; Gary Reynolds; Scott Davies; Nguyet -Thin Luu; Mohammed Alfaifi; Emma Shepherd; Yuri Boteon; Lorraine Wallace; Ye Htun Oo; David Adams; Darius F Mirza; H Mergentel; Gillian Muirhead; Barnaby Stephenson; Simon Afford

doi:10.1002/lt.25313

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

Ricky Bhogal, Christopher Weston, Susanne Velduis, Leuvenink Henri GD, Gary Reynolds, Scott Davies, Nguyet -Thin Luu, Mohammed Alfaifi, Emma Shepherd, Yuri Boteon, Lorraine Wallace, Ye Htun Oo, David Adams, Darius F Mirza, H Mergentel, Gillian Muirhead, Barnaby Stephenson, Simon Afford

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10 Citations (Scopus)

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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.

Original language	English
Journal	Liver Transplantation
Early online date	24 Jul 2018
DOIs	https://doi.org/10.1002/lt.25313
Publication status	E-pub ahead of print - 24 Jul 2018

Bibliographical note

From: Otto Schuck <onbehalfof@manuscriptcentral.com>
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

Keywords

Autophagy
Free radicals
Ischaemic liver injury
Necrosis

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10.1002/lt.25313Licence: None: All rights reserved

Bhogal_et_al_ROS-Mitophagy_Liver_Transplantation
This is the peer reviewed version of the following article: Ricky H. Bhogal, Christopher J. Weston, Susanne Velduis, Henri G.D. Leuvenink, Gary M. Reynolds, Scott Davies, Luu Nyguet Thin, Mohammed Alfaifi, Emma Shepard, Yuri Boteon, Lorraine Wallace, Ye Oo, David H. Adams, Darius F. Mirza, Hynek Mergental, Gillian Muirhead, Barnaby F. Stephenson, Simon C. Afford, The ROS‐Mitophagy Signalling Pathway Regulates Liver Endothelial Cell Survival during Ischaemia‐Reperfusion Injury, Liver Transplantation, [add volume/issue/page or article numbers], which has been published in final form at https://doi.org/10.1002/lt.25313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Checked 26/7/18.
Accepted author manuscript, 1.78 MBLicence: None: All rights reserved

Cite this

Bhogal, R., Weston, C., Velduis, S., Henri GD, L., Reynolds, G., Davies, S., Luu, N. -T., Alfaifi, M., Shepherd, E., Boteon, Y., Wallace, L., Oo, Y. H., Adams, D., Mirza, D. F., Mergentel, H., Muirhead, G., Stephenson, B., & Afford, S. (2018). The ROS-Mitophagy Signalling Pathway regulates liver endothelial cell survival during ischaemia-reperfusion injury. Liver Transplantation. Advance online publication. https://doi.org/10.1002/lt.25313

@article{2b505eae822642359f4b134537cb4c1e,

title = "The ROS-Mitophagy Signalling Pathway regulates liver endothelial cell survival during ischaemia-reperfusion injury",

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-dependentautophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.",

keywords = "Autophagy, Free radicals, Ischaemic liver injury, Necrosis",

author = "Ricky Bhogal and Christopher Weston and Susanne Velduis and {Henri GD}, Leuvenink and Gary Reynolds and Scott Davies and Luu, {Nguyet -Thin} and Mohammed Alfaifi and Emma Shepherd and Yuri Boteon and Lorraine Wallace and Oo, {Ye Htun} and David Adams and Mirza, {Darius F} and H Mergentel and Gillian Muirhead and Barnaby Stephenson and Simon Afford",

note = "From: Otto Schuck <onbehalfof@manuscriptcentral.com> 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 ",

year = "2018",

month = jul,

day = "24",

doi = "10.1002/lt.25313",

language = "English",

journal = "Liver Transplantation",

issn = "1527-6465",

publisher = "Wiley",

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Bhogal, R, Weston, C, Velduis, S, Henri GD, L, Reynolds, G , Davies, S , Luu, N-T, Alfaifi, M, Shepherd, E, Boteon, Y, Wallace, L , Oo, YH , Adams, D, Mirza, DF, Mergentel, H, Muirhead, G, Stephenson, B & Afford, S 2018, 'The ROS-Mitophagy Signalling Pathway regulates liver endothelial cell survival during ischaemia-reperfusion injury', Liver Transplantation. https://doi.org/10.1002/lt.25313

TY - JOUR

T1 - The ROS-Mitophagy Signalling Pathway regulates liver endothelial cell survival during ischaemia-reperfusion injury

AU - Bhogal, Ricky

AU - Weston, Christopher

AU - Velduis, Susanne

AU - Henri GD, Leuvenink

AU - Reynolds, Gary

AU - Davies, Scott

AU - Luu, Nguyet -Thin

AU - Alfaifi, Mohammed

AU - Shepherd, Emma

AU - Boteon, Yuri

AU - Wallace, Lorraine

AU - Oo, Ye Htun

AU - Adams, David

AU - Mirza, Darius F

AU - Mergentel, H

AU - Muirhead, Gillian

AU - Stephenson, Barnaby

AU - Afford, Simon

N1 - From: Otto Schuck <onbehalfof@manuscriptcentral.com> 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

PY - 2018/7/24

Y1 - 2018/7/24

N2 - 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-dependentautophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.

AB - 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-dependentautophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.

KW - Autophagy

KW - Free radicals

KW - Ischaemic liver injury

KW - Necrosis

U2 - 10.1002/lt.25313

DO - 10.1002/lt.25313

M3 - Article

SN - 1527-6465

JO - Liver Transplantation

JF - Liver Transplantation

ER -

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

Abstract

Bibliographical note

Keywords

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