Redox Regulation by Nuclear Factor Erythroid 2-Related Factor 2: Gatekeeping for the Basal and Diabetes-Induced Expression of Thioredoxin-Interacting Protein
Redox Regulation by Nuclear Factor Erythroid 2-Related Factor 2: Gatekeeping for the Basal and Diabetes-Induced Expression of Thioredoxin-Interacting Protein
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DOI：
10.1124/mol.112.081133
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发表时间：
2012-11-01
影响因子：
3.6
通讯作者：
Ma, Qiang
中科院分区：
文献类型：
--
作者：
He, Xiaoqing;Ma, Qiang
核因子红细胞2相关因子2（Nrf 2）是一种由一系列氧化剂和亲电子试剂激活的转录因子。Nrf 2对内源性氧化信号的转录应答在哺乳动物氧化还原生理学和氧化病理学中起着重要作用。高血压在心脏中诱导氧化应激，在那里它导致细胞凋亡并最终导致心肌病。在这里，我们研究了Nrf 2抑制糖尿病小鼠心脏氧化应激的机制。敲除（KO）的Nrf 2诱导的氧化应激和细胞凋亡KO心脏;糖尿病进一步增加氧化损伤。一个聚焦于通路的基因阵列显示，Nrf 2控制心脏中24个基因的表达，包括编码硫氧还蛋白相互作用蛋白（TXNIP）的基因。Nrf 2抑制心脏中Txnip的基础表达，并通过与Txnip启动子的抗氧化反应元件（ARE）（-1286至-1276）结合来阻断高糖对Txnip的诱导。Nrf 2与ARE的结合也抑制了MondoA与具有或不具有高葡萄糖的碳水化合物反应元件的结合。TXNIP通过抑制硫氧还蛋白促进活性氧的产生和细胞凋亡。另一方面，Nrf 2通过抑制Txnip增强硫氧还蛋白活性。研究结果首次揭示，Nrf 2是Txnip转录的关键守门人，抑制其基础表达和MondoA驱动的诱导，以控制糖尿病中的硫氧还蛋白氧化还原信号。
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor activated by a range of oxidants and electrophiles. The transcriptional response to endogenous oxidative cues by Nrf2 plays an important role in mammalian redox physiology and oxidative pathology. Hyperglycemia induces oxidative stress in the heart where it leads to apoptosis and ultimately cardiomyopathy. Here we investigated the mechanism by which Nrf2 suppresses oxidative stress in diabetic mouse heart. Knockout (KO) of Nrf2 induced oxidative stress and apoptosis in KO heart; diabetes further increased oxidative damage. A pathway-focused gene array revealed that Nrf2 controls the expression of 24 genes in the heart, including the gene encoding thioredoxin-interacting protein (TXNIP). Nrf2 suppressed the basal expression of Txnip in the heart and blocked induction of Txnip by high glucose by binding to an antioxidant response element (ARE) (-1286 to -1276) of the Txnip promoter. Binding of Nrf2 to ARE also suppressed the binding of MondoA to the carbohydrate response element with or without high glucose. TXNIP promoted reactive oxygen species production and apoptosis by inhibiting thioredoxin. On the other hand, Nrf2 boosted thioredoxin activity by inhibiting Txnip. The findings revealed, for the first time, that Nrf2 is a key gatekeeper of Txnip transcription, suppressing both its basal expression and MondoA-driven induction to control the thioredoxin redox signaling in diabetes.