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Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury
Author(s) -
Martin Juliette,
Romanque Pamela,
Maurhofer Olivier,
Schmitter Karin,
Hora Caroline,
Ferrand Gisèle,
Dufour JeanFrançois
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23978
Subject(s) - tumor necrosis factor alpha , apoptosis , reperfusion injury , nicotinamide adenine dinucleotide phosphate , biology , endocrinology , tumor necrosis factor receptor 1 , microbiology and biotechnology , heme oxygenase , medicine , chemistry , ischemia , immunology , cancer research , oxidase test , heme , biochemistry , tumor necrosis factor receptor , enzyme
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. Conclusion: The Hint1 protein influences the course of I/R injury, and its ablation in Kupffer cells may limit the extent of the injury. (H EPATOLOGY 2011)