Adenosine Diphosphate and the P2Y13 Receptor Are Involved in the Autophagic Protection of Ex Vivo Perfused Livers From Fasted Rats: Potential Benefit for Liver Graft Preservation.

Autor: Papegay B; Divisions of Experimental Medicine (ULB Unit 222), University Hospital Center, Charleroi, Belgium., Nuyens V; Divisions of Experimental Medicine (ULB Unit 222), University Hospital Center, Charleroi, Belgium., Albert A; Department of Biostatistics, University Hospital of Liège, Liège, Belgium., Cherkaoui-Malki M; BioPeroxIL Laboratory (Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism) EA 7270, University of Bourgogne-Franche Comté, Dijon, France., Andreoletti P; BioPeroxIL Laboratory (Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism) EA 7270, University of Bourgogne-Franche Comté, Dijon, France., Leo O; Laboratory of Immunobiology and ULB Centre for Research in Immunology (U-CRI), Free University of Brussels (ULB), Gosselies, Belgium., Kruys V; Molecular Biology of the Gene, Department of Molecular Biology, Free University of Brussels (ULB), Gosselies, Belgium., Boogaerts JG; Divisions of Experimental Medicine (ULB Unit 222), University Hospital Center, Charleroi, Belgium., Vamecq J; Inserm, and Hormonology/Metabolism/Nutrition/Oncology Department of the Centre of Biology and Pathology, Metabolism Branch, University Hospital Center of Lille and EA 7364-RADEME (Rare Developmental and Metabolic Disorders), North France University Lille, Lille, France.
Jazyk: angličtina
Zdroj: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society [Liver Transpl] 2021 Jul; Vol. 27 (7), pp. 997-1006. Date of Electronic Publication: 2021 Feb 17.
DOI: 10.1002/lt.25970
Abstrakt: Studies on how to protect livers perfused ex vivo can help design strategies for hepatoprotection and liver graft preservation. The protection of livers isolated from 24-hour versus 18-hour starved rats has been previously attributed to autophagy, which contributes to the energy-mobilizing capacity ex vivo. Here, we explored the signaling pathways responsible for this protection. In our experimental models, 3 major signaling candidates were considered in view of their abilities to trigger autophagy: high mobility group box 1 (HMGB1), adenosine monophosphate-activated protein kinase (AMPK), and purinergic receptor P2Y13. To this end, ex vivo livers isolated from starved rats were perfused for 135 minutes, after which perfusate samples were studied for protein release and biopsies were performed for evaluating signaling protein contents. For HMGB1, no significant difference was observed between livers isolated from rats starved for 18 and 24 hours at perfusion times of both 0 and 135 minutes. The phosphorylated and total forms of AMPK, but not their ratios, were significantly higher in 24-hour fasted than in 18-hour fasted livers. However, although the level of phosphorylated AMPK increased, perfusing ex vivo 18-hour fasted livers with 1 mM 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, did not protect the livers. In addition, the adenosine diphosphate (ADP; and not adenosine monophosphate [AMP]) to AMP + ADP + adenosine triphosphate ratio increased in the 24-hour starved livers compared with that in the 18-hour starved livers. Moreover, perfusing 24-hour starved livers with 0.1 mM 2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde (MRS2211), a specific antagonist of the P2Y13 receptor, induced an increase in cytolysis marker levels in the perfusate samples and a decrease in the levels of autophagic marker microtubule-associated proteins 1 light chain 3 II (LC3II)/actin (and a loss of p62/actin decrease), indicating autophagy inhibition and a loss of protection. The P2Y13 receptor and ADP (a physiological activator of this receptor) are involved in the protection of ex vivo livers. Therapeutic opportunities for improving liver graft preservation through the stimulation of the ADP/P2Y13 receptor axis are further discussed.
(Copyright © 2020 by the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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