Apoptosis

, Volume 18, Issue 5, pp 547–555 | Cite as

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

  • Z. Ben-Ari
  • Y. Issan
  • Y. Katz
  • M. Sultan
  • M. Safran
  • Laniado-Schwartzman Michal
  • G. Abraham Nader
  • R. Kornowski
  • F. Grief
  • O. Pappo
  • E. Hochhauser
Original Paper

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.

Keywords

Heme oxygenase-1 Cobalt-protoporphyrin Nuclear factor-kappaB (NF-κB) Ischemia reperfusion injury Liver 

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Z. Ben-Ari
    • 1
    • 2
    • 6
  • Y. Issan
    • 4
  • Y. Katz
    • 5
  • M. Sultan
    • 2
  • M. Safran
    • 2
  • Laniado-Schwartzman Michal
    • 7
  • G. Abraham Nader
    • 8
  • R. Kornowski
    • 4
  • F. Grief
    • 5
  • O. Pappo
    • 3
  • E. Hochhauser
    • 6
  1. 1.Liver Disease Center, Sheba Medical CenterRamat GanIsrael
  2. 2.Liver Research LaboratoryRamat GanIsrael
  3. 3.Department of HistopathologySheba Medical CenterRamat GanIsrael
  4. 4.Research Laboratory, Felsenstein Medical Research CenterPetach TiqwaIsrael
  5. 5.Department of Surgery ARabin Medical Center, Beilinson HospitalPetach TiqwaIsrael
  6. 6.Sackler School of Medicine, Tel Aviv UniversityTel AvivIsrael
  7. 7.Departments of PharmacologyNew York Medical CollegeValhallaUSA
  8. 8.Departments of PharmacologyJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonUSA

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