Long-term Dietary Nitrite and Nitrate Deficiency Causes the Metabolic Syndrome, Endothelial Dysfunction and Cardiovascular Death in Mice

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2017 Mar 30

PMID 28352942

Citations 31

Authors

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 Maeda

Yusuke Ohya

Masayuki Matsushita

Hiroaki Masuzaki

Akira Arasaki

Masato Tsutsui

Affiliations

Soon will be listed here.

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.

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