title: GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation.
abstract: We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia-reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention.
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain. daminzaouali12@yahoo.fr.|Research Unit of Biology and Molecular Anthropology Applied to Development and Health (UR12ES11), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia. daminzaouali12@yahoo.fr.|High Institute of Biotechnology of Monastir, University of Monastir, Monastir 5000, Tunisia. daminzaouali12@yahoo.fr.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain. arnau.panisello@iibb.csic.es.
authors.forename: Arnau
authors.initials: A
authors.lastname: Panisello
authors.affiliation: Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France. alexandregl.lopez@gmail.com.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lopez
authors.affiliation: Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France. ccastrob@gmail.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Castro
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain. emma.folch@iibb.csic.es.
authors.forename: Emma
authors.initials: E
authors.lastname: Folch
authors.affiliation: Department of Physiology, Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain. tcarbonell@ub.edu.
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.affiliation: Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal. anpiro@ci.uc.pt.
authors.forename: Anabela
authors.initials: A
authors.lastname: Rolo
authors.affiliation: Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal. palmeira@ci.uc.pt.
authors.forename: Carlos Marques
authors.initials: CM
authors.lastname: Palmeira
authors.affiliation: Hospital Clínico, Zaragoza 50009, Spain. agarciagil@telefonica.net.
authors.forename: Agustin
authors.initials: A
authors.lastname: Garcia-Gil
authors.affiliation: Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France. rene.adam@aphp.fr.
authors.forename: René
authors.initials: R
authors.lastname: Adam
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain. jrcbam@iibb.csic.es.
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D000818:Animals; D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D014292:Trimetazidine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D014665:Vasodilator Agents; D050994:Voltage-Dependent Anion Channels; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D014292:Trimetazidine
keywords: ER stress; GSK3β; IGL-1 preservation solution; VDAC; ischemia–reperfusion injury; liver transplantation; trimetazidine