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Redox regulation by Nrf2: gatekeeping for the basal and diabetes-induced expression of thioredoxin interacting protein.

Authors
He-X; Ma-Q
Source
Mol Pharmacol 2012 Nov; 82(5):887-897
NIOSHTIC No.
20041400
Abstract
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.
Keywords
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
Contact
Qiang Ma, National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505
CODEN
MOPMA3
Publication Date
20121101
Document Type
Journal Article
Email Address
qam1@cdc.gov
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
B09112012
Issue of Publication
5
ISSN
0026-895X
NIOSH Division
HELD
Source Name
Molecular Pharmacology
State
WV
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