title: Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury.
abstract: The identification of cellular pathways capable of limiting ischemia/reperfusion (I/R) injury remains a frontier in medicine, and its clinical relevance is urgent. Histidine triad nucleotide binding protein 1 (HINT1) is a tumor suppressor that influences apoptosis. Because apoptotic pathways are a feature of I/R injury, we asked whether Hint1 influences hepatic I/R injury. Hint1(-/-) and C57BL/6 mice were subjected to 70% liver ischemia followed by reperfusion for 3 or 24 hours or to a sham operation. The serum aminotransferase levels, histological lesions, apoptosis, reactive oxygen species, and expression of B cell lymphoma 2-associated X protein (Bax), heme oxygenase 1 (HO-1), interleukin-6 (IL-6), IL-10, tumor necrosis factor-a, Src, nuclear factor kappa B (p65/RelA), and c-Jun were quantified. The responses to toll-like receptor ligands and nicotinamide adenine dinucleotide phosphate oxidase activity in Kupffer cells were compared in Hint1(-/-) mice and C57BL/6 mice. After I/R, the levels of serum aminotransferases, parenchymal necrosis, and hepatocellular apoptosis were significantly lower in Hint1(-/-) mice versus control mice. Furthermore, Bax expression decreased more than 2-fold in Hint1(-/-) mice, and the increases in reactive oxygen species and HO-1 expression that were evident in wild-type mice after I/R were absent in Hint1(-/-) mice. The phosphorylation of Src and the nuclear translocation of p65 were increased in Hint1(-/-) mice, whereas the nuclear expression of phosphorylated c-Jun was decreased. The levels of the protective cytokines IL-6 and IL-10 were increased in Hint1(-/-) mice. These effects increased survival after I/R in mice lacking Hint1. Hint1(-/-) Kupffer cells were less activated than control cells after stimulation with lipopolysaccharides.
  
  
  CONCLUSIONS
  The Hint1 protein influences the course of I/R injury, and its ablation in Kupffer cells may limit the extent of the injury.
authors.affiliation: Institute of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland.
authors.forename: Juliette
authors.initials: J
authors.lastname: Martin
authors.forename: Pamela
authors.initials: P
authors.lastname: Romanque
authors.forename: Olivier
authors.initials: O
authors.lastname: Maurhofer
authors.forename: Karin
authors.initials: K
authors.lastname: Schmitter
authors.forename: Caroline
authors.initials: C
authors.lastname: Hora
authors.forename: Gisèle
authors.initials: G
authors.lastname: Ferrand
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000096:biosynthesis; D009336:Necrosis / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D000637:Transaminases / Q000097:blood; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D019061:src-Family Kinases / Q000096:biosynthesis
chemical_list: C489275:Hint1 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000637:Transaminases; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases