RGD Reference Report - Role of heme oxygenase 1 in TNF/TNF receptor-mediated apoptosis after hepatic ischemia/reperfusion in rats. - Rat Genome Database

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Role of heme oxygenase 1 in TNF/TNF receptor-mediated apoptosis after hepatic ischemia/reperfusion in rats.

Authors: Kim, SJ  Eum, HA  Billiar, TR  Lee, SM 
Citation: Kim SJ, etal., Shock. 2013 Apr;39(4):380-8. doi: 10.1097/SHK.0b013e31828aab7f.
RGD ID: 8661760
Pubmed: PMID:23423194   (View Abstract at PubMed)
DOI: DOI:10.1097/SHK.0b013e31828aab7f   (Journal Full-text)

Hepatocellular apoptosis commonly occurs in ischemia/reperfusion (I/R) injury. The binding of tumor necrosis factor (TNF) to TNF receptor 1 (TNFR1) leads to the formation of a death-inducing signaling complex (DISC), which subsequently initiates a caspase cascade resulting in apoptosis. Heme oxygenase 1 (HO-1) confers cytoprotection against cell death in I/R injury and inhibits stress-induced apoptotic pathways in vitro. This study investigated the role of HO-1 in modulating TNF/TNFR1-mediated cell death pathways in hepatic I/R injury. Rats were pretreated with hemin, an HO-1 inducer, and zinc protoporphyrin (ZnPP), an HO-1 inhibitor, before undergoing hepatic I/R. Heme oxygenase 1 activity increased after reperfusion. Ischemia/reperfusion-induced hepatocellular apoptosis was attenuated by hemin, as determined by the caspase-3 and -8 activity assays and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling). Zinc protoporphyrin eliminated the cytoprotective effect of hemin. Hepatic TNFR1 protein expression was unchanged among the experimental groups, whereas mitochondrial TNFR1 protein increased after I/R. Ischemia/reperfusion increased the quantity of DISC components, including TRADD (TNFR1-associated death domain), FADD (Fas-associated death domain), and caspase-8, as well as the assembly of DISCs within the liver. In the mitochondrial fraction, TNFR1-associated caspase-8 was increased after I/R. These increases were attenuated by hemin; zinc protoporphyrin eliminated this effect. Our findings suggest that the cytoprotective effects of HO-1 are mediated by suppression of TNF/TNFR1-mediated apoptotic signaling, specifically by modulating apoptotic DISC formation and mitochondrial TNFR1 translocation during hepatic I/R.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CASP8HumanLiver Reperfusion Injury treatmentISOCasp8 (Rattus norvegicus) RGD 
Casp8RatLiver Reperfusion Injury treatmentIEP  RGD 
Casp8MouseLiver Reperfusion Injury treatmentISOCasp8 (Rattus norvegicus) RGD 
FADDHumanLiver Reperfusion Injury treatmentISOFadd (Rattus norvegicus) RGD 
FaddRatLiver Reperfusion Injury treatmentIEP  RGD 
FaddMouseLiver Reperfusion Injury treatmentISOFadd (Rattus norvegicus) RGD 
TNFRSF1AHumanLiver Reperfusion Injury  ISOTnfrsf1a (Rattus norvegicus)protein:increased localization:mitochondrionRGD 
TRADDHumanLiver Reperfusion Injury treatmentISOTradd (Rattus norvegicus) RGD 
Tnfrsf1aRatLiver Reperfusion Injury  IEP protein:increased localization:mitochondrionRGD 
Tnfrsf1aMouseLiver Reperfusion Injury  ISOTnfrsf1a (Rattus norvegicus)protein:increased localization:mitochondrionRGD 
TraddRatLiver Reperfusion Injury treatmentIEP  RGD 
TraddMouseLiver Reperfusion Injury treatmentISOTradd (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Casp8  (caspase 8)
Fadd  (Fas associated via death domain)
Tnfrsf1a  (TNF receptor superfamily member 1A)
Tradd  (TNFRSF1A-associated via death domain)

Genes (Mus musculus)
Casp8  (caspase 8)
Fadd  (Fas associated via death domain)
Tnfrsf1a  (tumor necrosis factor receptor superfamily, member 1a)
Tradd  (TNFRSF1A-associated via death domain)

Genes (Homo sapiens)
CASP8  (caspase 8)
FADD  (Fas associated via death domain)
TNFRSF1A  (TNF receptor superfamily member 1A)
TRADD  (TNFRSF1A associated via death domain)


Additional Information