Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response.
Dietary nitrate, found in abundance in green vegetables, can be converted to the cytoprotective molecule nitrite by oral bacteria, suggesting that nitrate and nitrite may represent active cardioprotective constituents of the Mediterranean diet. We therefore tested the hypothesis that dietary nitrate and nitrite levels modulate tissue damage and ischemic gene expression in a mouse liver ischemia-reperfusion model. We found that stomach content, plasma, heart, and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion and could be restored to normal levels with nitrite supplementation in water. Remarkably, we confirmed that basal nitrite levels significantly reduced liver injury after ischemia-reperfusion. Consistent with an effect of nitrite on the posttranslational modification of complex I of the mitochondrial electron transport chain, the severity of liver infarction was inversely proportional to complex I activity after nitrite repletion in the diet. The transcriptional response of dietary nitrite after ischemia was more robust than after normoxia, suggesting a hypoxic potentiation of nitrite-dependent transcriptional signaling. Our studies indicate that normal dietary nitrate and nitrite levels modulate ischemic stress responses and hypoxic gene expression programs, supporting the hypothesis that dietary nitrate and nitrite are cytoprotective components of the diet.
Raat
Nicolaas J H
NJ
Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Noguchi
Audrey C
AC
Liu
Virginia B
VB
Raghavachari
Nalini
N
Liu
Delong
D
Xu
Xiuli
X
Shiva
Sruti
S
Munson
Peter J
PJ
Gladwin
Mark T
MT
D000825:Animal Structures / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004032:Diet; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects; D007511:Ischemia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D015427:Reperfusion Injury / Q000097:blood / Q000235:genetics / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites