NRF2 activation with Protandim attenuates salt-induced vascular dysfunction and microvascular rarefaction

Microcirculation. 2019 Oct;26(7):e12575. doi: 10.1111/micc.12575. Epub 2019 Jun 19.


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.

Keywords: NRF2; Protandim; antioxidants; cerebral circulation; endothelial dysfunction; oxidant stress; reactive oxygen species; resistance arteries; salt; sodium; superoxide dismutase; vascular dysfunction; vasodilation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arterioles
  • Drugs, Chinese Herbal / pharmacology*
  • Gene Expression Regulation, Developmental / drug effects
  • Male
  • Mesenteric Arteries / metabolism
  • Mesenteric Arteries / physiopathology
  • Mesocricetus
  • Microcirculation / drug effects
  • Middle Cerebral Artery / metabolism
  • Middle Cerebral Artery / physiopathology
  • NF-E2-Related Factor 2 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Chloride, Dietary / adverse effects*
  • Sodium Chloride, Dietary / pharmacology
  • Superoxide Dismutase / biosynthesis
  • Vascular Diseases* / chemically induced
  • Vascular Diseases* / metabolism
  • Vascular Diseases* / physiopathology
  • Vasodilation / drug effects*


  • Drugs, Chinese Herbal
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Protandim
  • Sodium Chloride, Dietary
  • Superoxide Dismutase
  • superoxide dismutase 2