ROLE OF HEME OXYGENASE 1 IN TNF/TNF RECEPTOR-MEDIATED APOPTOSIS AFTER HEPATIC ISCHEMIA/REPERFUSION IN RATS
ROLE OF HEME OXYGENASE 1 IN TNF/TNF RECEPTOR-MEDIATED APOPTOSIS AFTER HEPATIC ISCHEMIA/REPERFUSION IN RATS
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DOI：
10.1097/shk.0b013e31828aab7f
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发表时间：
2013-04-01
期刊：
影响因子：
3.1
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
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作者：
Kim, Seok-Joo;Eum, Hyun-Ae;Lee, Sun-Mee
肝细胞凋亡常发生在缺血/再灌注（I/R）损伤中。肿瘤坏死因子（TNF）与TNF受体1（TNFR 1）的结合导致死亡诱导信号复合物（DISC）的形成，其随后启动导致细胞凋亡的半胱天冬酶级联反应。血红素加氧酶1（HO-1）在体外可对I/R损伤中的细胞死亡提供细胞保护，并抑制应激诱导的凋亡途径。本研究探讨HO-1在调节TNF/TNFR 1介导的肝I/R损伤细胞死亡途径中的作用。在大鼠接受肝I/R之前，用血红素（HO-1诱导剂）和锌原卟啉（ZnPP）（HO-1抑制剂）预处理大鼠。再灌注后血红素氧合酶1活性增加。通过caspase-3和caspase-8活性测定和TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）测定，氯化血红素可减弱缺血/再灌注诱导的肝细胞凋亡。锌原卟啉可消除氯化血红素的细胞保护作用。肝TNFR 1蛋白表达在实验组中无变化，而线粒体TNFR 1蛋白在I/R后增加。缺血/再灌注增加了DISC组分的数量，包括TRADD（TNFR 1相关死亡结构域），FADD（Fas相关死亡结构域）和caspase-8，以及肝脏内DISC的组装。在线粒体组分中，TNFR 1相关的caspase-8在I/R后增加。这些增加被氯化血红素减弱;锌原卟啉消除了这种影响。我们的研究结果表明，HO-1的细胞保护作用是通过抑制TNF/TNFR 1介导的凋亡信号，特别是通过调节凋亡DISC的形成和线粒体TNFR 1易位在肝I/R。
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.