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Downregulation of the Nuclear Factor (Erythroid‐Derived 2)‐Like 2 (NRF2) Antioxidant Defense System Contributes to Endothelial Dysfunction and Microvascular Rarefaction with Elevated Dietary Salt Intake
Author(s) -
Lombard Julian H.,
Kautenburg Katie E.,
Priestley Jessica R. C.,
McCord Joe M.,
Greene Andrew S.,
Geurts Aron M.
Publication year - 2016
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.30.1_supplement.737.3
Subject(s) - endocrinology , angiotensin ii , endothelial dysfunction , medicine , microvessel , endothelium , chemistry , oxidative stress , microcirculation , downregulation and upregulation , renin–angiotensin system , arteriole , angiogenesis , biochemistry , blood pressure , gene
A high salt diet leads to vascular oxidant stress, endothelial dysfunction, and microvascular rarefaction, which can be ameliorated by chronic infusion of a low dose of angiotensin II (ANG II) or angiotensin (1–7) [ANG(1–7]. The present study investigated the role of the NRF2 antioxidant defense system in mediating the protective effect of ANG II and ANG (1–7) to ameliorate endothelial dysfunction and microvascular rarefaction occurring with elevated dietary salt intake. In these experiments, short term (3 days) high salt diet (4% NaCl) eliminated endothelium‐dependent dilation to acetylcholine (ACh) in isolated middle cerebral arteries (MCA) and reduced microvessel density (assessed with rhodamine‐labeled GS1 lectin) in the cremaster muscle of Sprague‐Dawley (S‐D) parental strain rats. The NRF2 inducers Protandim and sulforaphane restored ACh‐induced dilation of MCA and increased microvessel density in S‐D rats fed HS diet for 2 weeks. Deletion mutation of the Nrf2 gene utilizing TALEN technology eliminated the protective effect of ANG II infusion and significantly reduced the protective effect of ANG (1–7) infusion to restore ACh‐induced dilation of the MCA. The Nrf2 ( − / − ) mutation also eliminated the ability of ANG II and ANG (1–7) to prevent microvascular rarefaction in HS fed rats. Protandim restored endothelium dependent dilation to ACh in MCA of HS fed wild type controls, but not MCA of HS‐fed Nrf2 ( − / − ) mutant rats. These findings indicate that down regulation of NRF2‐mediated antioxidant defenses due to salt‐induced suppression of the renin‐angiotensin system leads to vascular oxidant stress, endothelial dysfunction, and microvascular rarefaction; and suggest that dietary upregulation of the NRF2 antioxidant system may be a valuable therapeutic approach to ameliorate endothelial dysfunction with HS diet and in low renin forms of salt‐sensitive hypertension. Support or Funding Information NIH #R‐01 HL65289‐12; #R56 HL65289‐13A1, and #R21 OD018309‐01