Transgenic Overexpression of Peroxiredoxin-2 Attenuates Ischemic Neuronal Injury Via Suppression of a Redox-Sensitive Pro-Death Signaling Pathway
Transgenic Overexpression of Peroxiredoxin-2 Attenuates Ischemic Neuronal Injury Via Suppression of a Redox-Sensitive Pro-Death Signaling Pathway
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DOI：
10.1089/ars.2011.4298
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发表时间：
2012-09-01
影响因子：
6.6
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Gan, Yu;Ji, Xunming;Chen, Jun
目的：过氧化物还毒素（peroxredoxins, PRXs）是一个新发现的过氧化氢清除酶家族，不仅有助于维持细胞氧化还原稳态，而且可能直接参与多种细胞内信号通路。PRX2是一种神经元特异性PRX，被认为参与多种神经退行性疾病的大脑抗氧化反应。本研究探讨PRX2在缺血性神经元损伤模型中的潜在神经保护作用及其机制。结果：与野生型小鼠相比，过表达PRX2的转基因小鼠在短暂局灶性脑缺血后3周内脑损伤减轻，神经功能恢复改善。在皮质神经元原代培养中，转染PRX2而不是失去催化位点的PRX2突变体，可以保护神经免受缺氧引起的细胞死亡。PRX2通过维持硫氧还蛋白（Trx）的还原状态，从而阻止氧化应激介导的凋亡信号调节激酶1 （ASK1）和下游MKK/JNK促死亡信号通路的激活，在缺血神经元中表现出强大的促存活作用。PRX2在Trx或ask1敲低的神经元培养物和JNK抑制剂处理的小鼠中不能提供额外的神经保护，以防止缺血性损伤。创新：本研究提供了证据，证明神经元过表达PRX2可延长脑缺血/再灌注损伤的神经保护。此外，结果表明PRX2通过信号通路抑制缺血诱导的神经元凋亡。结论：PRX2的表达和活性增强通过直接调节氧化还原敏感的Trx-ASK1信号复合物来保护缺血性神经元损伤。Antioxid。氧化还原信号，17,719-732。
Aims: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury. Results: Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx- or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor. Innovation: This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis. Conclusions: Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex. Antioxid. Redox Signal. 17, 719-732.