Details:

Alternative Title:
Mol Pharmacol
Personal Author:
He, Xiaoqing ; Ma, Qiang
He, Xiaoqing ; Ma, Qiang Less -
Description:
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.
Subject:
[+]
Animals
Apoptosis
Article
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cardiomyopathies
Carrier Proteins
Cell Line
Diabetes Mellitus, Experimental
Glucose
Male
Mice
Mice, Knockout
Myocardium
Myocytes, Cardiac
NF-E2-Related Factor 2
Oxidation-Reduction
Oxidative Stress
Protein Binding
Rats
Reactive Oxygen Species
Response Elements
Thioredoxins
Transcription, Genetic

Source:
Mol Pharmacol. 82(5):887-897
Pubmed ID:
22869588
Pubmed Central ID:
PMC4678870
Document Type:
Journal Article
Funding:
CC999999/Intramural CDC HHS/United States
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:ee9f765d68eedce771cee073a9fc0c242f624ced874065871c49c0ec95fca215
File Type:

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