Dietary nitrite attenuates oxidative stress and activates antioxidant genes in rat heart during hypobaric hypoxia

Nitric Oxide. 2012 Jan 1;26(1):61-73. doi: 10.1016/j.niox.2011.12.002. Epub 2011 Dec 14.


The nitrite anion represents the circulatory and tissue storage form of nitric oxide (NO) and a signaling molecule, capable of conferring cardioprotection and many other health benefits. However, molecular mechanisms for observed cardioprotective properties of nitrite remain largely unknown. We have evaluated the NO-like bioactivity and cardioprotective efficacies of sodium nitrite supplemented in drinking water in rats exposed to short-term chronic hypobaric hypoxia. We observed that, nitrite significantly attenuates hypoxia-induced oxidative stress, modulates HIF-1α stability and promotes NO-cGMP signaling in hypoxic heart. To elucidate potential downstream targets of nitrite during hypoxia, we performed a microarray analysis of nitrite supplemented hypoxic hearts and compared with both hypoxic and nitrite supplemented normoxic hearts respectively. The analysis revealed a significant increase in the expression of many antioxidant genes, transcription factors and cardioprotective signaling pathways which was subsequently confirmed by qRT-PCR and Western blotting. Conversely, hypoxia exposure increased oxidative stress, activated inflammatory cytokines, downregulated ion channels and altered expression of both pro- and anti-oxidant genes. Our results illustrate the physiological function of nitrite as an eNOS-independent source of NO in heart profoundly modulating the oxidative status and cardiac transcriptome during hypoxia.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Cyclic GMP / metabolism
  • Dietary Supplements
  • Gene Expression Regulation / drug effects
  • Heart / drug effects
  • Heart / physiopathology*
  • Hypoxia / diet therapy
  • Hypoxia / drug therapy
  • Hypoxia / genetics*
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Male
  • Myocardium / metabolism
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrites / pharmacology*
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Transcriptome


  • Antioxidants
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitrites
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Cyclic GMP