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Poly(ADP-ribose) Polymerase (PARP) is Critically Involved in Liver Ischemia/Reperfusion-injury

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Title: Poly(ADP-ribose) Polymerase (PARP) is Critically Involved in Liver Ischemia/Reperfusion-injury
Authors: Haga, Sanae Browse this author →KAKEN DB
Kanno, Akira Browse this author
Morita, Naoki Browse this author
Jin, Shigeki Browse this author
Matoba, Kotaro Browse this author →KAKEN DB
Ozawa, Takeaki Browse this author
Ozaki, Michitaka Browse this author →KAKEN DB
Keywords: Ischemia
reoxygenation Oxidative stress
Issue Date: 1-Feb-2022
Publisher: Elsevier
Journal Title: Journal of Surgical Research
Volume: 270
Start Page: 124
End Page: 138
Publisher DOI: 10.1016/j.jss.2021.09.008
PMID: 34656890
Abstract: Background: Poly(ADP-ribose) polymerase (PARP) is a DNA-repairing enzyme activated by extreme genomic stress, and therefore is potently activated in the remnant liver suffering from ischemia after surgical resection. However, the impact of PARP on post-ischemic liver injury has not been elucidated yet. Materials and methods: We investigated the impact of PARP on murine hepatocyte/liver injury induced by hypoxia/ischemia, respectively. Results: PJ34, a specific inhibitor of PARP, markedly protected against hypoxia/reoxygenation (H/R)-induced cell death, though z-VAD-fmk, a pan-caspase inhibitor similarly showed the protective effect. PJ34 did not affect H/R-induced caspase activity or caspase-mediated cell death. z-VAD-fmk also did not affect the production of PAR (i.e., PARP activity). Therefore, PARPand caspase-mediated cell death occurred in a mechanism independent of each other in H/R. H/R immediately induced activation of PARP and cell death afterwards, both of which were suppressed by PJ34 or Trolox, an antioxidant. This suggests that H/R-induced cell death occurred redox-dependently through PARP activation. H/R and OS induced nuclear translocation of apoptosis inducing factor (AIF, a marker of parthanatos) and RIP1-RIP3 interaction (a marker of necroptosis), both of which were suppressed by PJ34. H/R induced PARPmediated parthanatos and necroptosis redox-dependently. In mouse experiments, PJ34 significantly reduced serum levels of AST, ALT & LDH and areas of hepatic necrosis after liver ischemia/reperfusion, similar to z-VAD-fmk or Trolox. Conclusion: PARP, activated by ischemic damage and/or oxidative stress, may play a critical role in post-ischemic liver injury by inducing programmed necrosis (parthanatos and necroptosis). PARP inhibition may be one of the promising strategies against post-ischemic liver injury.
Rights: © 2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 尾崎 倫孝

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