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The Reactive Oxygen Species-Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury.

Authors :
Bhogal RH
Weston CJ
Velduis S
G D Leuvenink H
Reynolds GM
Davies S
Nyguet-Thin L
Alfaifi M
Shepard EL
Boteon Y
Wallace L
Oo YH
Adams DH
Mirza DF
Mergental H
Muirhead G
Stephenson BTF
Afford SC
Source :
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society [Liver Transpl] 2018 Oct; Vol. 24 (10), pp. 1437-1452.
Publication Year :
2018

Abstract

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.<br /> (© 2018 by the American Association for the Study of Liver Diseases.)

Details

Language :
English
ISSN :
1527-6473
Volume :
24
Issue :
10
Database :
MEDLINE
Journal :
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
Publication Type :
Academic Journal
Accession number :
30040176
Full Text :
https://doi.org/10.1002/lt.25313