The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis
The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis
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DOI：
10.1089/ars.2014.6237
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发表时间：
2015-12-01
影响因子：
6.6
通讯作者：
De Franceschi, Lucia
中科院分区：
文献类型：
--
作者：
Matte, Alessandro;De Falco, Luigia;De Franceschi, Lucia
目的：地中海贫血是一种常见的遗传性红细胞疾病，以无效的红细胞生成和严重的氧化应激为特征。过氧化还蛋白-2(Prx2)是一种典型的2-半胱氨酸过氧化还蛋白，在地中海贫血的红细胞生成过程中表达上调，但其在应激性红细胞生成中的作用尚未完全确定。结果：在这里，我们发现Prx2(-/-)小鼠在红细胞生成中表现出与Hbb(th3/+)小鼠相似的与氧化还原反应转录因子红系2(Nrf2)激活相关的活性氧相关的异常。我们产生了遗传性缺乏Prx2的地中海贫血小鼠(Prx2(-/-)Hbb(th3/+))，并记录了严重无效红细胞生成的地中海贫血血液学表型恶化。为了进一步验证Prx2在应激性红细胞生成中的关键作用，我们给Hbb(th3/+)小鼠注射融合重组PEP1Prx2，并记录了无效红细胞生成的减少。我们进一步证明Prx2的作用是通过激活NRF2和上调保护氧化损伤的基因，如谷胱甘肽S转移酶、血红素加氧酶-1和NADPH脱氢酶-1来实现的。创新：我们提出Prx2是一个关键的抗氧化系统，而Nrf2的激活是一个细胞对氧化应激做出反应的适应性过程，导致确保细胞生存所需的抗氧化剂(抗氧化反应元件)基因上调。结论：我们的数据揭示了通过Prx2和Nrf2在应激性红细胞生成过程中的相互作用来对抗氧化损伤的适应性机制，并提出了通过调节内源性抗氧化系统来减少无效红细胞生成的新的治疗方案。抗氧化剂。氧化还原信号。23,1284-1297。
Aims: -Thalassemia is a common inherited red cell disorder characterized by ineffective erythropoiesis and severe oxidative stress. Peroxiredoxin-2 (Prx2), a typical 2-cysteine peroxiredoxin, is upregulated during -thalassemic erythropoiesis, but its contribution to stress erythropoiesis, a common feature of thalassemia, is yet to be fully defined. Results: Here, we showed that Prx2(-/-) mice displayed reactive oxygen species related abnormalities in erythropoiesis similar to that of Hbb(th3/+) mice associated with activation of redox response transcriptional factor nuclear factor-erythroid 2 (Nrf2). We generated -thalassemic mice genetically lacking Prx2 (Prx2(-/-)Hbb(th3/+)) and documented a worsened -thalassemic hematological phenotype with severe ineffective erythropoiesis. To further validate a key role of Prx2 in stress erythropoiesis, we administrated fused recombinant PEP1Prx2 to Hbb(th3/+) mice and documented a decrease in ineffective erythropoiesis. We further show that Prx2 effects are mediated by activation of Nrf2 and upregulation of genes that protect against oxidative damage such as gluthatione S-transferase, heme-oxygenase-1, and NADPH dehydrogenase quinone-1. Innovation: We propose Prx2 as a key antioxidant system and Nrf2 activation is a cellular adaptive process in response to oxidative stress, resulting in upregulation of antioxidant (antioxidant responsive element) genes required to ensure cell survival. Conclusion: Our data shed new light on adaptive mechanisms against oxidative damage through the interplay of Prx2 and Nrf2 during stress erythropoiesis and suggest new therapeutic options to decrease ineffective erythropoiesis by modulation of endogenous antioxidant systems. Antioxid. Redox Signal. 23, 1284-1297.