PMID- 30040176 OWN - NLM STAT- MEDLINE DCOM- 20190624 LR - 20231213 IS - 1527-6473 (Electronic) IS - 1527-6465 (Linking) VI - 24 IP - 10 DP - 2018 Oct TI - The Reactive Oxygen Species-Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury. PG - 1437-1452 LID - 10.1002/lt.25313 [doi] AB - 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. CI - (c) 2018 by the American Association for the Study of Liver Diseases. FAU - Bhogal, Ricky H AU - Bhogal RH AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. AD - The Liver Unit, University Hospitals of Birmingham, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. FAU - Weston, Christopher J AU - Weston CJ AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Velduis, Susanne AU - Velduis S AD - University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. FAU - G D Leuvenink, Henri AU - G D Leuvenink H AD - University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. FAU - Reynolds, Gary M AU - Reynolds GM AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Davies, Scott AU - Davies S AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Nyguet-Thin, Luu AU - Nyguet-Thin L AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Alfaifi, Mohammed AU - Alfaifi M AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Shepard, Emma L AU - Shepard EL AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Boteon, Yuri AU - Boteon Y AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Wallace, Lorraine AU - Wallace L AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Oo, Ye H AU - Oo YH AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Adams, David H AU - Adams DH AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Mirza, Darius F AU - Mirza DF AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. AD - The Liver Unit, University Hospitals of Birmingham, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. FAU - Mergental, Hynek AU - Mergental H AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. AD - The Liver Unit, University Hospitals of Birmingham, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. FAU - Muirhead, Gillian AU - Muirhead G AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Stephenson, Barnaby T F AU - Stephenson BTF AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. FAU - Afford, Simon C AU - Afford SC AD - Centre for Liver Research, School of Infection and Immunity, Institute for Biomedical Research, The Medical School, Birmingham, United Kingdom. LA - eng GR - G1002552/MRC_/Medical Research Council/United Kingdom GR - MR/J011509/1/MRC_/Medical Research Council/United Kingdom GR - RCZV18746/Wellcome Trust/United Kingdom GR - RCHX14183/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Liver Transpl JT - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society JID - 100909185 RN - 0 (Atg7 protein, mouse) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - EC 6.2.1.45 (ATG7 protein, human) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) SB - IM MH - Animals MH - Autophagy/physiology MH - Autophagy-Related Protein 7/genetics/metabolism MH - Cell Survival MH - Disease Models, Animal MH - Endothelial Cells/*physiology MH - Gene Knockdown Techniques MH - Humans MH - Liver/cytology/surgery MH - Liver Transplantation/*adverse effects MH - Mice MH - Mice, Inbred C57BL MH - Mitochondria/metabolism MH - Mitophagy/*physiology MH - Primary Cell Culture MH - RNA, Small Interfering/metabolism MH - Reactive Oxygen Species/*metabolism MH - Reperfusion Injury/etiology/*pathology MH - Signal Transduction/physiology EDAT- 2018/07/25 06:00 MHDA- 2019/06/25 06:00 CRDT- 2018/07/25 06:00 PHST- 2017/12/11 00:00 [received] PHST- 2018/04/29 00:00 [revised] PHST- 2018/06/04 00:00 [accepted] PHST- 2018/07/25 06:00 [pubmed] PHST- 2019/06/25 06:00 [medline] PHST- 2018/07/25 06:00 [entrez] AID - 10.1002/lt.25313 [doi] PST - ppublish SO - Liver Transpl. 2018 Oct;24(10):1437-1452. doi: 10.1002/lt.25313.