Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner
Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner
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DOI：
10.1016/j.taap.2008.04.019
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发表时间：
2008-09-15
影响因子：
3.8
通讯作者：
Jeong, Hye Gwang
中科院分区：
文献类型：
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作者：
Hwang, Yong Pil;Kim, Hyung Gyun;Jeong, Hye Gwang
锌结合蛋白金属硫蛋白-III（MT-III）与神经元损伤的抗性有关。然而，其影响的潜在机制尚不清楚。在这项研究中，我们证明，MT-III防止积累的活性氧（ROS）在多巴胺能SH-SY 5 Y细胞的挑战与帕金森氏病相关的神经毒素6-羟基多巴胺（6-OHDA）的机制，涉及磷脂酰肌醇3-激酶（PI 3 K）和ERK激酶/NF-E2相关因子2（Nrf 2）依赖诱导应激反应蛋白血红素加氧酶-1（HO-1）。用MT-III预处理SH-SY 5 Y细胞显著降低了6-OHDA诱导的ROS产生、caspase-3活化和随后的细胞死亡。此外，MT-III上调HO-1表达，这种表达赋予神经保护作用，对抗6-OHDA诱导的氧化损伤。此外，MT-III诱导Nrf 2核转位，这是MT-III诱导的HO-1表达的上游，以及PI 3 K和ERK 1/2激活，这是一种参与诱导的Nrf 2核转位、HO-1表达和神经保护的途径。综上所述，这些结果表明PI 3 K和ERK/Nrf 2信号通路通过调节抗氧化酶HO-1的表达来控制细胞内ROS水平。(C)2008年爱思唯尔公司All rights reserved.
The zinc-binding protein metallothionein-III (MT-III) is associated with resistance to neuronal injury. However, the underlying mechanism for its effects is unclear. In this study, we demonstrate that MT-III prevents the accumulation of reactive oxygen species (ROS) in dopaminergic SH-SY5Y cells challenged with the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA) by a mechanism that involves phosphatidylinositol 3-kinase (PI3K) and ERK kinase/NF-E2-related factor 2 (Nrf2) dependent induction of the stress response protein heme oxygenase-1 (HO-1). Pretreatment of SH-SY5Y cells with MT-III significantly reduced 6-OHDA-induced generation of ROS, caspase-3 activation, and subsequent cell death. Also, MT-III up-regulates HO-1 expression and this expression confers neuroprotection against oxidative injury induced by 6-OHDA. Moreover, MT-III induces Nrf2 nuclear translocation, which is upstream of MT-III-induced HO-1 expression, and PI3K and ERK1/2 activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. Taken together, these results suggest that the PI3K and ERK/Nrf2 signaling pathway controls the intracellular levels of ROS by regulating the expression of the antioxidant enzyme HO-1. (C) 2008 Elsevier Inc. All rights reserved.