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Repetitive ROS Inhibits Nrf2 Antioxidant Defense in Ischemic Heart Failure
Author(s) -
Benipal Simranjeet Singh,
Liu Tingting,
Knowlton Anne
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1080.19
Subject(s) - oxidative stress , keap1 , antioxidant , reactive oxygen species , myocyte , downregulation and upregulation , in vivo , cardiac function curve , heart failure , chemistry , oxidative phosphorylation , microbiology and biotechnology , medicine , pharmacology , biology , biochemistry , transcription factor , gene , genetics
Nrf2, the master regulator for the antioxidant response, is critical for protecting the heart against reactive oxygen species (ROS). Normally, Nrf2 is bound to Kelch‐like ECH‐associated protein 1 (Keap1) and ubiquitinated in the cytosol. With increased oxidative stress, Nrf2 is released from Keap1, and moves into nucleus, binding to the antioxidant response element (ARE) in target gene promoters. This results in increased expression of antioxidant genes. Ischemic heart failure (IHF), a major cause of cardiovascular morbidity and mortality, is an inflammatory, chronic disease characterized by increased oxidative stress and progressive loss of ventricular function; however, we found Nrf2 expression was decreased by 50% in this disease. The interesting question is does Nrf2 inactivation with corresponding failure of antioxidant response contribute to the progression of IHF? We hypothesized that repetitive ROS exposure in IHF results in depression of Nrf2 activity, which as Nrf2 also regulates its own expression will in turn lead to decreased Nrf2. H 2 O 2 is a major contributor to oxidative stress and damage thus is ideal to investigate the circumstances that occur in vivo due to ROS. Repetitive ROS treatments (modeling the chronic condition) reduced Nrf2 levels by 50% compared to a single treatment. In experiments with isolated rat adult cardiac myocytes treated with repetitive ROS treatments, immunohistochemistry revealed Nrf2 failed to traffic to the nucleus. Downregulation of Nrf2 in IHF and in isolated adult cardiac myocytes after repetitive ROS treatment was associated with decreased Nrf2 nucleus binding activity, suggesting inhibition of the Nrf2 mediated antioxidant defense. Further work evaluated changes in gene expression and mitochondrial function with the reduction of Nrf2. Support or Funding Information This work was supported by the following: APS Undergraduate Research Fellowship (UGSRF); NIH RO1 HL079071; VA, Merit Review, 5101BX000839; and NIH R01 HL085844.