Heme Oxygenase-1 Protects Human Melanocytes from H2O2-Induced Oxidative Stress via the Nrf2-ARE Pathway
Heme Oxygenase-1 Protects Human Melanocytes from H2O2-Induced Oxidative Stress via the Nrf2-ARE Pathway
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DOI：
10.1038/jid.2011.56
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发表时间：
2011-07-01
影响因子：
6.5
通讯作者：
Gao, Tianwen
中科院分区：
文献类型：
--
作者：
Jian, Zhe;Li, Kai;Gao, Tianwen
过氧化氢(H_2O_2)引起的氧化应激导致细胞死亡，与白癜风的发病机制有关。核因子E2相关因子2(NRF2)-抗氧化反应元件(ARE)是主要的抗氧化途径，调节氧化应激相关的细胞保护基因。我们假设Nrf2-ARE途径通过诱导下游的抗氧化基因来保护人黑素细胞免受过氧化氢诱导的氧化损伤。因此，我们使用Nrf2短干扰RNA(SiRNA)和pCMV6-XL5-Nrf2在永生化的人黑素细胞系PIG1中下调或上调Nrf2的表达。然后在不同的氧化应激条件下分析黑素细胞的细胞活力和凋亡。我们的研究表明，HO-1是过氧化氢处理后PIG1细胞中诱导最多的抗氧化剂基因。抑制Nrf2或锌原卟啉IX(ZnPP)处理增加了H_2O_2引起的黑素细胞死亡，而上调Nrf_2或氯化血红素处理则减少了H_2O_2引起的黑素细胞死亡。此外，在原代培养的人黑素细胞中，通过检测Nrf2和HO-1的表达和转位，证实了过氧化氢诱导的Nrf2-ARE/HO-1途径。这些数据表明，调节Nrf2/HO-1通路可以减轻过氧化氢诱导的人黑素细胞的氧化损伤。我们的数据表明，HO-1通过Nrf2-ARE途径保护人类黑素细胞免受氧化损伤。
Oxidative stress caused by hydrogen peroxide (H2O2) leads to cell death and has been implicated in the pathogenesis of vitiligo. The nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE), a major antioxidant pathway, regulates oxidative stress-related cytoprotective genes. We hypothesized that the Nrf2-ARE pathway protects human melanocytes from H2O2-induced oxidative damage through the induction of downstream antioxidative genes. Thus, we used Nrf2 short interfering RNA (siRNA) and pCMV6-XL5-Nrf2 to downregulate or upregulate Nrf2 expression in immortalized human melanocyte cell line PIG1. The melanocytes were then analyzed under different oxidative stress conditions for cell viability and apoptosis. Our study demonstrated that heme oxygenase-1 (HO-1) was the most induced antioxidant gene in PIG1 cells after treatment with H2O2. Knockdown of Nrf2 or zinc protoporphyrin IX (ZnPP) treatment increased cell death caused by H2O2 in melanocytes, but upregulation of Nrf2 or hemin treatment reduced cell death caused by H2O2 in melanocytes. In addition, the H2O2-induced Nrf2-ARE/HO-1 pathway was confirmed in primary cultured human melanocytes by examining the expression and translocation of Nrf2 and HO-1. These data suggested that regulation of the Nrf2/HO-1 pathway can reduce H2O2-induced oxidative damage in human melanocytes. Our data demonstrate that HO-1 protects human melanocytes from oxidative damage via the Nrf2-ARE pathway.