Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage.
Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage.
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DOI：
10.1016/j.freeradbiomed.2011.12.006
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发表时间：
2012-03-01
影响因子：
7.4
通讯作者：
Cao W
中科院分区：
文献类型：
--
作者：
Wang B;Zhu X;Kim Y;Li J;Huang S;Saleem S;Li RC;Xu Y;Dore S;Cao W
对基于组蛋白去乙酰化酶（HDAC）的疗法作为中风的潜在治疗的兴趣急剧增长。HDAC抑制的神经保护作用可能涉及多种机制，包括不依赖于组蛋白的转录因子乙酰化的调节。转录因子Nrf 2作为抗氧化剂应答基因的关键调节因子，已被证明在中风中具有保护作用。在这里，我们假设HDAC抑制可能通过激活Nrf 2通路提供对小鼠脑缺血的神经保护。我们确定经典HDAC抑制剂阿司他汀A增加了缺氧缺糖后神经元细胞的活力（OD值从0.10±0.01增加到0.25±0.08），并减少了中风野生型小鼠的梗死体积（从49.1±3.8减少到21.3±4.6%）。体外研究表明，HDAC抑制减少Nrf 2抑制因子Keap 1的表达，诱导Keap 1/Nrf 2解离，Nrf 2核转位，Nrf 2与血红素加氧酶1（HO 1）中的抗氧化反应元件结合，并引起HO 1转录。此外，我们证明了HDAC抑制上调Nrf 2下游的蛋白质，包括HO 1，NAD（P）H：醌氧化还原酶1和谷氨酸-半胱氨酸连接酶催化亚基在神经元培养物和脑组织中。最后，与野生型小鼠不同，Nrf 2缺陷小鼠在脑缺血后不受HDAC药理学抑制的保护。我们的研究表明，Nrf 2的激活可能是HDAC抑制提供神经保护的重要机制。
Interest in histone deacetylase (HDAC)-based therapeutics as a potential treatment for stroke has grown dramatically. The neuroprotection of HDAC inhibition may involve multiple mechanisms, including modulation of transcription factor acetylation independent of histones. The transcription factor Nrf2 has been shown to be protective in stroke as a key regulator of antioxidant-responsive genes. Here, we hypothesized that HDAC inhibition might provide neuroprotection against mouse cerebral ischemia by activating the Nrf2 pathway. We determined that the classic HDAC inhibitor trichostatin A increased neuronal cell viability after oxygen-glucose deprivation (from an OD value of 0.10±0.01 to 0.25±0.08) and reduced infarct volume in wild-type mice with stroke (from 49.1±3.8 to 21.3±4.6%). In vitro studies showed that HDAC inhibition reduced Nrf2 suppressor Keap1 expression, induced Keap1/Nrf2 dissociation, Nrf2 nuclear translocation, and Nrf2 binding to antioxidant response elements in heme oxygenase 1 (HO1), and caused HO1 transcription. Furthermore, we demonstrated that HDAC inhibition upregulated proteins downstream of Nrf2, including HO1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit in neuron cultures and brain tissue. Finally, unlike wild-type mice, Nrf2-deficient mice were not protected by pharmacologic inhibition of HDAC after cerebral ischemia. Our studies suggest that activation of Nrf2 might be an important mechanism by which HDAC inhibition provides neuroprotection.
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影响因子：
6.1
作者：
Correa, Fernando;Mallard, Carina;Nilsson, Michael;Sandberg, Mats
通讯作者：
Sandberg, Mats
影响因子：
6.1
作者：
Petri, S;Kiaei, M;Beal, MF
通讯作者：
Beal, MF
影响因子：
5.3
作者：
Chen, Jia-Shiong;Huang, Po-Hsun;Chen, Jaw-Wen
通讯作者：
Chen, Jaw-Wen
DOI：
10.1124/jpet.107.120188
发表时间：
2007-06-01
影响因子：
3.5
作者：
Kim, Hyeon Ju;Rowe, Michael;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
DOI：
10.1084/jem.20071728
发表时间：
2008-06-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cao W;Bao C;Padalko E;Lowenstein CJ
通讯作者：
Lowenstein CJ