Heavy chain ferritin acts as an anti-apoptotic gene that protects livers from ischemia-reperfusion injury
Heavy chain ferritin acts as an anti-apoptotic gene that protects livers from ischemia-reperfusion injury
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DOI：
10.1096/fj.03-0229fje
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发表时间：
2003-07-01
期刊：
影响因子：
4.8
通讯作者：
Soares, MP
中科院分区：
文献类型：
--
作者：
Berberat, PO;Katori, M;Soares, MP
血红素加氧酶-1（HO-1）在多种促氧化条件下被诱导，例如与移植器官的缺血再灌注损伤（IRI）相关的那些条件。HO-1切割血红素卟啉环释放Fe 2+，这诱导Fe 2+螯合蛋白铁蛋白的表达。通过限制Fe 2+通过芬顿反应参与自由基生成的能力，铁蛋白充当抗氧化剂。我们以前已经表明HO-1保护移植器官免受IRI。我们已经将这种保护作用与HO-1的抗凋亡作用联系起来。铁蛋白的铁结合特性是否有助于HO-1的保护作用尚不清楚。我们现在报告，重组腺病毒介导的铁蛋白重链（H-铁蛋白）基因的过表达保护大鼠肝脏IRI，并防止肝细胞损伤后移植到同基因受体。H-铁蛋白的保护作用与抑制内皮细胞和肝细胞凋亡有关。H-铁蛋白保护培养的内皮细胞免受各种刺激诱导的凋亡。这些发现揭示了H-铁蛋白的抗凋亡功能，并表明H-铁蛋白可以用于治疗的方式，以防止肝脏IRI，从而最大限度地增加用于移植的器官供体库。
Heme oxygenase-1 (HO-1) is induced under a variety of pro-oxidant conditions such as those associated with ischemia-reperfusion injury (IRI) of transplanted organs. HO-1 cleaves the heme porphyrin ring releasing Fe2+, which induces the expression of the Fe2+ sequestering protein ferritin. By limiting the ability of Fe2+ to participate in the generation of free radicals through the Fenton reaction, ferritin acts as an anti-oxidant. We have previously shown that HO-1 protects transplanted organs from IRI. We have linked this protective effect with the anti-apoptotic action of HO-1. Whether the iron-binding properties of ferritin contributed to the protective effect of HO-1 was not clear. We now report that recombinant adenovirus mediated overexpression of the ferritin heavy chain (H-ferritin) gene protects rat livers from IRI and prevents hepatocellular damage upon transplantation into syngeneic recipients. The protective effect of H-ferritin is associated with the inhibition of endothelial cell and hepatocyte apoptosis in vivo. H-ferritin protects cultured endothelial cells from apoptosis induced by a variety of stimuli. These findings unveil the anti-apoptotic function of H-ferritin and suggest that H-ferritin can be used in a therapeutic manner to prevent liver IRI and thus maximize the organ donor pool used for transplantation.