Regulation of Vascular Redox State by Thioredoxin

硫氧还蛋白是活性氧的强力清除剂。硫氧还蛋白相互作用蛋白（Txnip;也称为 称为VDUP 1或维生素D3上调蛋白1）结合硫氧还蛋白，现在已知是一种 硫氧还蛋白活性重要抑制剂。我们先前已经证明Txnip本身是一个氧化还原敏感基因 一种会损害细胞存活的蛋白质产物此外，Txnip过表达阻断细胞生长， 反应，并且生长因子信号如PDGF需要Txnip的降解，以便允许硫氧还蛋白介导的免疫应答。 转录活性因此，令人信服的证据已经出现，Txnip，一个默默无闻的孤儿， 基因产物，是多种信号事件的关键调节因子，由于其直接抑制 硫氧还蛋白活性由于细胞内硫氧还蛋白水平趋于恒定，因此Txnip可能是一个关键， 控制细胞内氧化还原状态的机制。活性氧物质参与了许多阶段， 动脉粥样硬化在这里，我们提出了关于硫氧还蛋白/Txnip在血管内皮细胞中的潜在重要性的初步数据。 并描述其在加速动脉粥样硬化中的潜在作用。一个有趣的新发现是， 许多刺激抑制Txnip，从而增加硫氧还蛋白活性，葡萄糖强烈诱导Txnip，并抑制 硫氧还蛋白活性在体外和体内。我们提出的中心假设，即调控的探索 Txnip损害血管硫氧还蛋白活性，导致氧化应激增加并促进动脉粥样硬化。 由于葡萄糖诱导Txnip，这些实验与糖尿病血管疾病特别相关。我们 描述了三个假设驱动的目的，将探索Txnip在体外血管病理生理学中的作用 和体内。目标是： 目标1.为了验证葡萄糖诱导Txnip促进血管内皮细胞凋亡的假设， 细胞通过阻断硫氧还蛋白的抗氧化功能。 目标2.为了使用组织特异性荧光定量分析来验证Txnip调节小鼠糖尿病动脉中氧化还原状态的假设， 靶向基因缺失方法。 目标3。目的：验证Txnip的调节参与动脉粥样硬化的发生发展的假说。

Thioredoxin is a powerful scavenger of reactive oxygen species. Thioredoxin-interacting protein (Txnip; also known as VDUP1 or Vitamin D3 Up-regulated Protein 1) binds to thioredoxin and is now known to be an important inhibitor of thioredoxin activity. We have previously shown that Txnip is itself a redox-sensitive gene with a protein product that impairs cell survival. Furthermore, Txnip overexpression blocks cellular growth responses, and growth factor signals such as PDGF require degradation of Txnip in order to allow thioredoxinmediated transcriptional activity. Thus, compelling evidence has now emerged that Txnip, an obscure orphan gene product only a few years ago, is a critical regulator of diverse signaling events due to its direct inhibition of thioredoxin activity. Because intracellular thioredoxin levels tend to be constant, Txnip may therefore be a key mechanism for controlling intracellular redox state. Reactive oxygen species participate in many stages of atherosclerosis. Here we present preliminary data on the potential importance of Thioredoxin/Txnip in vascular disease and describe its potential role in accelerating atherosclerosis. An intriguing new finding is that while many stimuli suppress Txnip and thus increase thioredoxin activity, glucose robustly induces Txnip and inhibits thioredoxin activity both in vitro and in vivo. We propose exploration of the central hypothesis that regulation of Txnip impairs vascular thioredoxin activity, leading to increased oxidative stress and promoting atherosclerosis. Because glucose induces Txnip, these experiments have particular relevance to diabetic vascular disease. We describe three hypothesis-driven Aims that will explore the role of Txnip in vascular pathophysiology in vitro and in vivo. The Aims are: Aim 1. To test the hypothesis that the induction of Txnip by glucose promotes a pro-apoptotic state in vascular cells through blockade of thioredoxin's antioxidant function. Aim 2. To test the hypothesis that Txnip regulates redox state in diabetic arteries in mice using tissue-specific targeted gene deletion approaches. Aim 3. To test the hypothesis that regulation of Txnip participates in the promotion of atherosclerosis.