Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice

Mika Kina-Tanada, Mayuko Sakanashi, Akihide Tanimoto, Tadashi Kaname, Toshihiro Matsuzaki, Katsuhiko Noguchi, Taro Uchida, Junko Nakasone, Chisayo Kozuka, Masayoshi Ishida, Haruaki Kubota, Yuji Taira, Yuichi Totsuka, Shin ichiro Kina, Hajime Sunakawa, Junichi Omura, Kimio Satoh, Hiroaki Shimokawa, Nobuyuki Yanagihara, Shiro MaedaYusuke Ohya, Masayuki Matsushita, Hiroaki Masuzaki, Akira Arasaki, Masato Tsutsui

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


Aims/hypothesis: Nitric oxide (NO) is synthesised not only from l-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. Methods: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of l-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Results: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. Conclusions/interpretation: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Original languageEnglish
Pages (from-to)1138-1151
Number of pages14
Issue number6
Publication statusPublished - 2017 Jun 1


  • Acute myocardial infarction
  • Cardiovascular death
  • Diet
  • Endothelial dysfunction
  • Metabolic syndrome
  • Mice
  • Nitrate
  • Nitric oxide
  • Nitrite

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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