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Effect of NRF2 Activation on Endothelial Function, Microvessel Density, and Gene Expression in Rats fed High Salt Diet
Author(s) -
Uche Nnamdi,
Kozak Kaleigh,
Fink Katie,
McCord Joe,
Lombard Julian H.
Publication year - 2018
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.2018.32.1_supplement.846.12
Subject(s) - oxidative stress , endocrinology , endothelial dysfunction , medicine , vascular endothelial growth factor , endothelium , downregulation and upregulation , antioxidant , biology , chemistry , biochemistry , gene , vegf receptors
BACKGROUND High salt (HS) diet promotes vascular oxidative stress and endothelial dysfunction in animal models and humans. Studies in animals indicate that salt‐induced suppression of antioxidant defense mechanisms plays a crucial role in endothelial dysfunction, microvascular rarefaction and vascular oxidative stress. We hypothesized that activation of the master antioxidant transcription factor nuclear factor (erythroid‐derived 2)‐like‐2 (NRF2) with the dietary supplement Protandim protects against salt‐induced vascular dysfunction and microvascular rarefaction by restoring redox homeostasis. OBJECTIVE To determine whether activation of Nrf2 via dietary supplementation with Protandim will prevent salt‐induced endothelial dysfunction, vascular oxidative stress, and microvascular rarefaction via effects on antioxidant enzyme expression. METHODS Age‐matched, male Sprague‐Dawley rats (12–15 weeks old) were fed a high salt (HS; 4.0% NaCl) diet ± ~60 mg/kg/day Protandim supplement for 2 weeks. mRNA from harvested liver samples was used for real time PCR evaluation of the effects of Nrf2 upregulation on a range of genes related to oxidative stress, as reported in the literature. Changes in protein expression were evaluated via Western blotting. RESULTS Protandim treatment restored endothelium‐dependent dilation to acetylcholine in middle cerebral arteries, reduced mitochondrial ROS levels (Mito‐SOX) in basilar arteries, and increased microvessel density in the cremaster muscle of HS‐fed rats. Protandim supplementation increased mRNA levels of thioredoxin reductase 1 (n=6, p=0.008), reduced mRNA expression of the pro‐oxidative transcription factor Kruppel‐like factor 9 (Klf9) (n=6, p < 0.001) and tended to increase the expression of mRNA for glutathione reductase (GSR) and catalase in liver samples compared to untreated rats fed HS diet alone. Other indicators were not significantly changed by Protandim treatment, either by qPCR or Western blot analysis. CONCLUSIONS Treatment of HS‐fed rats with the Nrf2 activator Protandim ameliorates salt‐induced endothelial dysfunction, vascular oxidative stress, and microvascular rarefaction via complex effects on enzymes and proteins affecting redox state. Support or Funding Information NIH #R01‐HL128242 and # R21‐OD018309‐JHL This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .