Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide
Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide
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DOI：
10.1016/j.bbrc.2008.07.061
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发表时间：
2008-10-10
影响因子：
3.1
通讯作者：
Chen-Roetling, Jing
中科院分区：
文献类型：
--
作者：
Regan, Raymond F.;Li, Zhi;Chen-Roetling, Jing
铁调节蛋白（IRP）-1和IRP 2通过与其mRNA的5 '非翻译区中的铁反应元件结合来抑制铁蛋白合成。本研究测试了缺乏这些蛋白质的神经元将抵抗过氧化氢（H2 O2）毒性的假设。用100-300 μ M H2 O2处理的野生型皮质培养物持续广泛的神经元死亡，如通过乳酸脱氢酶测定所测量的，并且丙二醛显著增加。在IRP 2敲除培养物中，两个终点均降低超过85%。IRP 1基因缺失有一个较弱的和可变的影响，约20%的细胞死亡减少在300 μ M H2 O2。与野生型相比，在IRP 1和IRP 2敲除培养物中，H2 O2处理后铁蛋白表达分别增加了1.9倍和6.7倍。这些结果表明，铁调节蛋白，特别是IRP 2，增加神经元对氧化损伤的脆弱性。靶向IRP 2与铁蛋白mRNA结合的疗法可以减轻由于氧化应激引起的神经元损失。(C)2008年爱思唯尔公司All rights reserved.
Iron regulatory Protein (IRP)-1 and IRP2 inhibit ferritin synthesis by binding to an iron responsive element in the 5'-untranslated region of its mRNA. The present study tested the hypothesis that neurons lacking these proteins would be resistant to hydrogen peroxide (H2O2) toxicity. Wild-type cortical cultures treated with 100-300 mu M H2O2 sustained widespread neuronal death, as measured by lactate dehydrogenase assay, and a significant increase in malondialdehyde. Both endpoints were reduced by over 85% in IRP2 knockout Cultures. IRP1 gene deletion had a weaker and variable effect, with approximately 20% reduction in cell death at 300 mu M H2O2. Ferritin expression after H2O2 treatment was increased 1.9- and 6.7-fold in IRP1 and IRP2 knockout Cultures, respectively, compared with wild-type. These results suggest that iron regulatory proteins, particularly IRP2, increase neuronal Vulnerability to oxidative injury. Therapies targeting IRP2 binding to ferritin mRNA may attenuate neuronal loss due to oxidative stress. (C) 2008 Elsevier Inc. All rights reserved.