Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress
Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress
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DOI：
10.1016/j.bbagen.2015.09.018
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发表时间：
2015-12-01
影响因子：
3
通讯作者：
Hung, Kuan-Yu
中科院分区：
文献类型：
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作者：
Cheng, Hui-Teng;Yen, Chung-Jen;Hung, Kuan-Yu
血红素加氧酶-1（HO-1）具有保护细胞免受损伤的作用，但其酶促产物铁可能促进自由基的产生，这一现象长期以来一直令人困惑。在这里，我们建立了铁蛋白重链（FHC）和HO-1之间的功能连接。在人类狼疮性肾炎中，HO-1和FHC共定位于肾小球内。在啮齿动物抗Thy 1（胸腺细胞抗原1）诱导的肾小球肾炎中，血红素加氧酶阻断降低FHC的表达并加速系膜细胞死亡。在培养的大鼠肾小球系膜细胞中，血红素加氧酶的刺激增强了其对过氧化氢的抵抗力，而RNA干扰敲低FHC则损害了这种有益的作用。HO-1的RNA干扰使细胞更容易受到过氧化氢的影响，这可以通过强制表达野生型FHC而不是失去铁储存能力和铁氧化酶活性的突变体来挽救。在这些细胞中，JunD的磷酸化没有持续。微阵列分析确定了四个可能调控HO-1诱导的FHC转录的候选转录因子。我们的研究结果支持FHC在中和铁毒性以及介导HO-1在响应氧化应激中的保护作用中的作用。(C)2015 Elsevier B. V.版权所有。
The phenomenon that heme oxygenase-1 (HO-1) protects cell from injury yet its enzymatic product, iron, may facilitate generation of free radical has been long puzzling. Here we establish a functional connection between ferritin heavy chain (FHC) and HO-1. In human lupus nephritis HO-1 and FHC are colocalized within the glomeruli. In rodent anti-Thy1 (thymocyte antigen 1) induced glomerulonephritis, heme oxygenase blockade lowers the expression of FHC and accelerates mesangial cell death. Stimulation of heme oxygenase in cultured rat mesangial cell enhances its resistance to hydrogen peroxide, whereas FHC knockdown by RNA interference compromises this salutary effect. RNA interference of HO-1 makes the cell more susceptible to hydrogen peroxide, which can be rescued by forced expression of wild-type FHC but not mutants that lose the capacity of iron storage and ferroxidase activity. Phosphorylation of JunD was not sustained in these cells. Microarray analysis identifies four candidate transcriptional factors that may regulate the HO-1-induced transcription of FHC. Our results support the role of FHC in neutralizing the iron toxicity as well as mediating the protective effect of HO-1 in response to oxidative stress. (C) 2015 Elsevier B.V. All rights reserved.