title: Role of heme oxygenase 1 in TNF/TNF receptor-mediated apoptosis after hepatic ischemia/reperfusion in rats.
abstract: 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.
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors: Seok-Joo
authors: SJ
authors: Kim
authors: Hyun-Ae
authors: HA
authors: Eum
authors: Timothy R
authors: TR
authors: Billiar
authors: Sun-Mee
authors: SM
authors: Lee
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001663:Bilirubin / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D008099:Liver / Q000098:blood supply*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000502:physiology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; C017803:zinc protoporphyrin; D045304:Cytochromes c; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase; D053181:Caspase 8; D020170:Caspase 1; D001663:Bilirubin