title: Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury.
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.
authors: Liver Disease Center, Sheba Medical Center, Tel Hashomer, 52620, Ramat Gan, Israel. ziv.ben-ari@sheba.health.gov.il
authors: Z
authors: Z
authors: Ben-Ari
authors: Y
authors: Y
authors: Issan
authors: Y
authors: Y
authors: Katz
authors: M
authors: M
authors: Sultan
authors: M
authors: M
authors: Safran
authors: Laniado-Schwartzman
authors: LS
authors: Michal
authors: G Abraham
authors: GA
authors: Nader
authors: R
authors: R
authors: Kornowski
authors: F
authors: F
authors: Grief
authors: O
authors: O
authors: Pappo
authors: E
authors: E
authors: Hochhauser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D011524:Protoporphyrins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*
chemical_list: D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3