Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia, USA.
Mol Pharmacol. 2012 Nov;82(5):887-97. doi: 10.1124/mol.112.081133. Epub 2012 Aug 6.
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.
核因子红细胞 2 相关因子 2（Nrf2）是一种转录因子，可被多种氧化剂和电子受体激活。Nrf2 对内源性氧化信号的转录反应在哺乳动物氧化还原生理学和氧化病理中起着重要作用。高血糖会在心脏中引起氧化应激，从而导致细胞凋亡并最终导致心肌病。在这里，我们研究了 Nrf2 抑制糖尿病小鼠心脏氧化应激的机制。Nrf2 敲除（KO）会在 KO 心脏中诱导氧化应激和细胞凋亡；糖尿病进一步增加了氧化损伤。一个以通路为重点的基因阵列表明，Nrf2 控制着心脏中 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。Nrf2 抑制了心脏中 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）结合来阻止高葡萄糖诱导的 Txnip 诱导。Nrf2 与 ARE 的结合也抑制了 MondoA 在有或没有高葡萄糖的情况下与碳水化合物反应元件的结合。Txnip 通过抑制硫氧还蛋白来促进活性氧的产生和细胞凋亡。另一方面，Nrf2 通过抑制 Txnip 来增强硫氧还蛋白的活性。这些发现首次揭示了 Nrf2 是 Txnip 转录的关键守门员，它抑制 Txnip 的基础表达和 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。
