Thioredoxin is a powerful scavenger of reactive oxygen species. Thioredoxin-interacting protein (Txnip; alsoknown as VDUP1 or Vitamin D3 Up-regulated Protein 1) binds to thioredoxin and is now known to be animportant inhibitor of thioredoxin activity. We have previously shown that Txnip is itself a redox-sensitive genewith a protein product that impairs cell survival. Furthermore, Txnip overexpression blocks cellular growthresponses, and growth factor signals such as PDGF require degradation of Txnip in order to allow thioredoxinmediatedtranscriptional activity. Thus, compelling evidence has now emerged that Txnip, an obscure orphangene product only a few years ago, is a critical regulator of diverse signaling events due to its direct inhibition ofthioredoxin activity. Because intracellular thioredoxin levels tend to be constant, Txnip may therefore be a keymechanism for controlling intracellular redox state. Reactive oxygen species participate in many stages ofatherosclerosis. Here we present preliminary data on the potential importance of Thioredoxin/Txnip in vasculardisease and describe its potential role in accelerating atherosclerosis. An intriguing new finding is that whilemany stimuli suppress Txnip and thus increase thioredoxin activity, glucose robustly induces Txnip and inhibitsthioredoxin activity both in vitro and in vivo. We propose exploration of the central hypothesis that regulation ofTxnip 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. Wedescribe three hypothesis-driven Aims that will explore the role of Txnip in vascular pathophysiology in vitroand in vivo.
The Aims are:
Aim 1. To test the hypothesis that the induction of Txnip by glucose promotes a pro-apoptotic state in vascularcells 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-specifictargeted gene deletion approaches.
Aim 3. To test the hypothesis that regulation of Txnip participates in the promotion of atherosclerosis.
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