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Diabetologia. 2017 Jun;60(6):1138-1151. doi: 10.1007/s00125-017-4259-6. Epub 2017 Mar 28.

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

Author information

1
Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
2
Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
3
Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
4
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
5
Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
6
Regenerative Medicine Research Center, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
7
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
8
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
9
Third Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
10
Department of Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
11
Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan. tsutsui@med.u-ryukyu.ac.jp.

Abstract

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.

KEYWORDS:

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

PMID:
28352942
DOI:
10.1007/s00125-017-4259-6
[Indexed for MEDLINE]

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