Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity.
Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity.
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DOI：
10.1371/journal.pone.0101044
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kostura MJ
中科院分区：
文献类型：
--
作者：
Attucks OC;Jasmer KJ;Hannink M;Kassis J;Zhong Z;Gupta S;Victory SF;Guzel M;Polisetti DR;Andrews R;Mjalli AM;Kostura MJ
氧化应激是由活性氧（ROS）在代谢活动和环境因素的作用下产生的。氧化应激的增加与广泛的炎症性疾病的病理生理有关。细胞对过量ROS的反应涉及抗氧化反应元件（ARE）基因的诱导，这些基因受转录激活因子Nrf2和转录抑制因子Bach1的控制。开发能够激活保护性抗氧化反应网络的合成小分子具有重要的治疗意义。传统的靶向受调控基因激活的小分子药物（如巴多洛酮、富马酸二甲酯）通过烷基化包括Nrf2控制蛋白Keap1在内的多种蛋白来发挥作用。另一种方法是靶向抑制物Bach1。Bach1有一个内源性配体，血红素，可以抑制Bach1与ARE的结合，从而允许nrf2介导的基因表达，包括血红素加氧酶-1 (HMOX1)，这是Bach1抑制的一个很好的靶标。在本报告中，我们使用正常的人肺成纤维细胞来筛选一组合成的小分子，以了解它们诱导HMOX1的能力。发现了一类以HPP-4382为代表的hmox1诱导化合物。这些化合物不是反应性亲电试剂，不受n -乙酰半胱氨酸的抑制，也不干扰ROS或细胞谷胱甘肽。利用RNAi，我们进一步证明了HPP-4382以nrf2依赖的方式诱导HMOX1。染色质免疫沉淀证实，HPP-4382处理NHLF细胞可以相互协调Bach1结合的减少和Nrf2与HMOX1 E2增强子结合的增加。最后，我们发现HPP-4382可以抑制Bach1活性的报告基因实验，该实验测量由人类HMOX1 E2增强子驱动的转录。我们的研究结果表明，HPP-4382通过调节Bach1与靶基因ARE结合位点的结合，是一种新的抗氧化反应激活剂。
Oxidative stress is generated by reactive oxygen species (ROS) produced in response to metabolic activity and environmental factors. Increased oxidative stress is associated with the pathophysiology of a broad spectrum of inflammatory diseases. Cellular response to excess ROS involves the induction of antioxidant response element (ARE) genes under control of the transcriptional activator Nrf2 and the transcriptional repressor Bach1. The development of synthetic small molecules that activate the protective anti-oxidant response network is of major therapeutic interest. Traditional small molecules targeting ARE-regulated gene activation (e.g., bardoxolone, dimethyl fumarate) function by alkylating numerous proteins including Keap1, the controlling protein of Nrf2. An alternative is to target the repressor Bach1. Bach1 has an endogenous ligand, heme, that inhibits Bach1 binding to ARE, thus allowing Nrf2-mediated gene expression including that of heme-oxygenase-1 (HMOX1), a well described target of Bach1 repression. In this report, normal human lung fibroblasts were used to screen a collection of synthetic small molecules for their ability to induce HMOX1. A class of HMOX1-inducing compounds, represented by HPP-4382, was discovered. These compounds are not reactive electrophiles, are not suppressed by N-acetyl cysteine, and do not perturb either ROS or cellular glutathione. Using RNAi, we further demonstrate that HPP-4382 induces HMOX1 in an Nrf2-dependent manner. Chromatin immunoprecipitation verified that HPP-4382 treatment of NHLF cells reciprocally coordinated a decrease in binding of Bach1 and an increase of Nrf2 binding to the HMOX1 E2 enhancer. Finally we show that HPP-4382 can inhibit Bach1 activity in a reporter assay that measures transcription driven by the human HMOX1 E2 enhancer. Our results suggest that HPP-4382 is a novel activator of the antioxidant response through the modulation of Bach1 binding to the ARE binding site of target genes.
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影响因子：
14.9
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
通讯作者：
Biswal S
影响因子：
5.3
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
2.2
作者：
Iida, Akio;Inagaki, Koji;Igarashi, Kazuhiko
通讯作者：
Igarashi, Kazuhiko
影响因子：
5
作者：
Johns, Douglas G.;Zelent, Dorothy;Jaye, Michael C.
通讯作者：
Jaye, Michael C.
影响因子：
4.8
作者：
Hintze, Korry J.;Katoh, Yasutake;Theil, Elizabeth C.
通讯作者：
Theil, Elizabeth C.