1. Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-Reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain.
- Author
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Concors SJ, Hernandez PT, O'Brien C, DePaolo J, Murken DR, Aufhauser DD, Wang Z, Xiong Y, Krumeich L, Ge G, Beier UH, Bhatti TR, Kozikowski AP, Avelar LAA, Kurz T, Hancock WW, and Levine MH
- Subjects
- Animals, Male, Disease Models, Animal, Mice, Aspartate Aminotransferases blood, Alanine Transaminase blood, Indoles pharmacology, Indoles therapeutic use, Histone Deacetylases metabolism, Histone Deacetylases genetics, Warm Ischemia adverse effects, Ubiquitin metabolism, Reperfusion Injury prevention & control, Reperfusion Injury metabolism, Reperfusion Injury etiology, Histone Deacetylase 6 antagonists & inhibitors, Histone Deacetylase 6 metabolism, Histone Deacetylase 6 genetics, Histone Deacetylase Inhibitors pharmacology, Liver drug effects, Liver pathology, Liver blood supply, Liver metabolism, Mice, Inbred C57BL, Mice, Knockout, Hydroxamic Acids pharmacology, Liver Transplantation adverse effects
- Abstract
Background: Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation., Methods: Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors., Results: Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage ( P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI ( P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia ( P < 0.01 for AST and P < 0.01 for ALT)., Conclusions: Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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