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Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury

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Abstract

Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)–dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB’s regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation.

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Author information

Authors and Affiliations

  1. Liver Disease Center, Sheba Medical Center, Tel Hashomer, 52620, Ramat Gan, Israel

    Z. Ben-Ari

  2. Liver Research Laboratory, Tel Hashomer, 52620, Ramat Gan, Israel

    Z. Ben-Ari, M. Sultan & M. Safran

  3. Department of Histopathology, Sheba Medical Center, Tel Hashomer, 52620, Ramat Gan, Israel

    O. Pappo

  4. Research Laboratory, Felsenstein Medical Research Center, Petach Tiqwa, Israel

    Y. Issan & R. Kornowski

  5. Department of Surgery A, Rabin Medical Center, Beilinson Hospital, Petach Tiqwa, Israel

    Y. Katz & F. Grief

  6. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Z. Ben-Ari & E. Hochhauser

  7. Departments of Pharmacology, New York Medical College, Valhalla, NY, USA

    Laniado-Schwartzman Michal

  8. Departments of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

    G. Abraham Nader

Authors
  1. Z. Ben-Ari
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  2. Y. Issan
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  3. Y. Katz
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  4. M. Sultan
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  6. Laniado-Schwartzman Michal
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  7. G. Abraham Nader
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  8. R. Kornowski
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  9. F. Grief
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  10. O. Pappo
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  11. E. Hochhauser
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Corresponding author

Correspondence to Z. Ben-Ari.

Additional information

O. Pappo and E. Hochhauser are two last co authors.

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Ben-Ari, Z., Issan, Y., Katz, Y. et al. Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury. Apoptosis 18, 547–555 (2013). https://doi.org/10.1007/s10495-013-0814-x

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  • DOI: https://doi.org/10.1007/s10495-013-0814-x

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