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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 | | reperfusion | | PARP | | Parthanatos | | Necroptosis | | Hypoxia | | 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 http://creativecommons.org/licenses/by-nc-nd/4.0/ | | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/87826 |
| 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)
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Submitter: 尾崎 倫孝
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