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Modulation of glutathione hemostasis by inhibition of 12/15-lipoxygenase prevents ROS-mediated cell death after hepatic ischemia and reperfusion.
Oxid. Med. Cell. Longev. 2017:8325754 (2017)
BACKGROUND: Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. METHODS: Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. RESULTS: TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. CONCLUSION: Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Rat-liver Transplantation; Ischemia/reperfusion Injury; Oxidative Stress; Warm Ischemia; Molecular-mechanisms; Dimethyl-sulfoxide; Scutellaria-baicalensis; Cold Ischemia; Ferroptosis; Apoptosis
ISSN (print) / ISBN
1942-0900
e-ISSN
1942-0900
Quellenangaben
Volume: 2017,
Article Number: 8325754
Publisher
Landes Bioscience
Publishing Place
Austin, Tex.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Developmental Genetics (IDG)