Hypothesis This study tested the hypothesis that dietary activation of the master antioxidant and cell protective transcription factor nuclear factor, erythroid ‐2‐like 2 (NRF2), protects against salt‐induced vascular dysfunction by restoring redox homeostasis in the vasculature. Methods Male Sprague‐Dawley rats and Syrian hamsters were fed a HS (4.0% NaCl) diet containing ~60 mg/kg/day Protandim supplement for 2 weeks and compared to controls fed HS diet alone. Results Protandim supplementation restoredendothelium‐dependent vasodilation in response to acetylcholine (ACh) in middle cerebral arteries (MCA)of HS‐fed rats and hamster cheek pouch arterioles, and increased microvessel density in the cremastermuscle of HS‐fed rats. The restored dilation to ACh in MCA of Protandim‐treated rats was prevented by inhibiting nitric oxide synthase (NOS) with L‐NAME [100 μM] and was absent in MCA from Nrf2(−/−) knockout rats fed HS diet. Basilar arteries from HS‐fed rats treated with Protandim exhibited significantly lower staining for mitochondrial oxidizing species than untreated animals fed HS diet alone; and Protandim treatment increased MnSOD (SOD2) protein expression in mesenteric arteries of HS‐fed rats. Conclusions These results suggest that dietary activation of NRF2 protects against salt‐induced vascular dysfunction, vascular oxidative stress, and microvascular rarefaction by upregulating antioxidant defenses and reducing mitochondrial ROS levels.
The master antioxidant and cell protective transcription factor nuclear factor (erythroid‐derived 2)‐like‐2 (Nrf2) plays a key role in maintaining redox homeostasis by binding to antioxidant response elements (ARE) in the promoter regions of multiple antioxidant genes. The goal of these experiments was to determine whether direct activation of Nrf2‐mediated antioxidant defenses with Protandim (~40 mg/m2 per day for 2 weeks): 1) ameliorates endothelial dysfunction and oxidative stress in cerebral arteries of Dahl salt‐sensitive (SS) rats fed high salt (HS; 4% NaCl) diet; 2) improves renal function; and 3), increases skeletal muscle microvessel density in HS‐fed SS rats. Protandim treatment restored endothelium‐dependent vasodilation in response to acetylcholine (ACh) in the middle cerebral artery (MCA) of SS rats fed HS diet, but failed to increase skeletal muscle microvessel density or improve glomerular injury scores. Nrf2 activation also led to elevated urinary albumin levels and increased protein casting in renal tubules of HS‐fed SS rats. Protandim downregulated the expression of the pro‐oxidative transcription factor Kruppel‐like factor 9 (Klf9) in cerebral arteries but upregulated Klf9 expression in kidneys of HS‐fed SS rats fed HS diet. These findings support the hypothesis that pharmacological activation of Nrf2 during high and sustained levels of oxidative stress can have either beneficial effects (cerebral arteries) or detrimental effects that may be mediated by upregulation of Klf9 (kidney). These differential effects could have contributed to the failure of the BEACON clinical trial involving Nrf2 activation in patients with type 2 diabetes and advanced (stage 4) kidney disease; and may provide safety guidelines for therapeutic administration of Nrf2 activators in conditions characterized by elevated oxidative stress.Support or Funding InformationNIH #R01‐HL128242 and #R21‐OD018309‐JHLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
BACKGROUNDHigh 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.OBJECTIVETo 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.METHODSAge‐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.RESULTSProtandim 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.CONCLUSIONSTreatment 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 InformationNIH #R01‐HL128242 and # R21‐OD018309‐JHLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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