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Molecular Pharmacology

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Research ArticleArticle

Redox Regulation by Nuclear Factor Erythroid 2-Related Factor 2: Gatekeeping for the Basal and Diabetes-Induced Expression of Thioredoxin-Interacting Protein

Xiaoqing He and Qiang Ma
Molecular Pharmacology November 2012, 82 (5) 887-897; DOI: https://doi.org/10.1124/mol.112.081133
Xiaoqing He
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
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Qiang Ma
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
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Abstract

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.

Footnotes

  • This work was supported by the National Institute for Occupational Safety and Health.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.081133.

  • ABBREVIATIONS:

    ROS
    reactive oxygen species
    Trx
    thioredoxin
    Prx
    peroxiredoxin
    TXNIP
    thioredoxin interacting protein
    ChoRE
    carbohydrate response element
    Nrf2
    nuclear factor erythroid 2-related factor 2
    ARE
    antioxidant response element
    KO
    knockout
    WT
    wild-type
    STZ
    streptozotocin
    AMVM
    adult mouse ventricular myocytes
    KHB
    Krebs-Henseleit bicarbonate buffer
    8-OHdG
    8-hydroxydeoxyquanine
    DAPI
    4′,6-diamidino-2-phenylindole
    DHE
    dihydroethium
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    siRNA
    small interfering RNA
    ChIP
    chromatin immunoprecipitation.

  • Received July 10, 2012.
  • Accepted August 6, 2012.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

Suppression of TXNIP Expression by Nrf2

Xiaoqing He and Qiang Ma
Molecular Pharmacology November 1, 2012, 82 (5) 887-897; DOI: https://doi.org/10.1124/mol.112.081133

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Research ArticleArticle

Suppression of TXNIP Expression by Nrf2

Xiaoqing He and Qiang Ma
Molecular Pharmacology November 1, 2012, 82 (5) 887-897; DOI: https://doi.org/10.1124/mol.112.081133
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