Redox regulation by Nrf2: gatekeeping for the basal and diabetes-induced expression of thioredoxin interacting protein.
Mol Pharmacol 2012 Nov; 82(5):887-897
Nrf2 is a transcription factor activated by a range of oxidants and electrophiles. 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. 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 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 ROS 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 gate keeper of Txnip transcription, suppressing both its basal expression and MondoA-driven induction to control the thioredoxin redox signaling in diabetes.
Oxidative-processes; Physiology; Pathology; Heart; Cardiac-function; Cardiovascular-disease; Cardiovascular-function; Cardiovascular-system; Cardiovascular-system-disease; Cardiovascular-system-disorders; Laboratory-animals; Genes; Carbohydrates; Oxidation-reduction-reactions;
Author Keywords: Oxidation/reduction; Promoter analysis; Regulation - transcriptiona; Oxidative stress/antioxidants; Toxicant-induced gene express; Oxidative stress
Qiang Ma, National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505