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The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury
Author(s) -
Bhogal Ricky H.,
Weston Christopher J.,
Velduis Susanne,
G. D. Leuvenink Henri,
Reynolds Gary M.,
Davies Scott,
NyguetThin Luu,
Alfaifi Mohammed,
Shepard Emma L.,
Boteon Yuri,
Wallace Lorraine,
Oo Ye H.,
Adams David H.,
Mirza Darius F.,
Mergental Hynek,
Muirhead Gillian,
Stephenson Barnaby T. F.,
Afford Simon C.
Publication year - 2018
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.25313
Subject(s) - autophagy , mitophagy , reactive oxygen species , reperfusion injury , microbiology and biotechnology , programmed cell death , liver injury , gene knockdown , necrosis , mitochondrial ros , liver transplantation , medicine , mitochondrion , cancer research , transplantation , biology , ischemia , apoptosis , pharmacology , pathology , biochemistry
Ischemia/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 activate 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. 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. During IRI, ROS specifically activate autophagy‐related protein (ATG) 7 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, small interfering RNA 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. In conclusion, these findings demonstrate that during liver IRI ROS‐dependent autophagy promotes the survival of LEC, and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.