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PO2-7-24

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

[Speaker] Masato Tsutsui:1
[Co-author] Mika Kina-Tanada:1,4, Mayuko Sakanashi:1, Toshihiro Matsuzaki:1, Katsuhiko Noguchi:1, Junko Nakasone:1, Hiroaki Shimokawa:2, Yusuke Ohya:3, Akira Arasaki:4
1:Department of Pharmacology, Ryukyu University Graduate School of Medicine, Japan, 2:Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan, 3:Third Dept Intern Med, Ryukyu University Graduate School of Medicine, Japan, 4:Department of Dental Surgery, Ryukyu University Graduate School of Medicine, Japan

Background: Nitric oxide (NO) is synthesized not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate (NOx). Green leafy vegetables are abundant in nitrate, however whether or not a deficiency in dietary NOx spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary NOx deficiency induces metabolic syndrome (MetS) in mice.
Methods and Results: To this end, we prepared a low NOx diet (LND) consisting of a low NOx chow in which the contents of L-arginine, fat, carbohydrates, protein, and calorie were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. The LND or a regular diet (RD) was administered in male wild-type (WT) C57BL/6 mice (n=6-24). We previously reported that plasma NOx levels were extremely low in mice lacking all three NOSs, suggesting a minor role of the exogenous NO production system. However, the LND for 3 months resulted in a marked decrease in plasma NOx levels in the WT mice. The LND markedly reduced endothelial NOS (eNOS) expression levels in the visceral fat, accounting for the markedly lower plasma NOx levels in the WT mice fed the LND. The LND did not affect food intake. However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidemia, and glucose intolerance; 18 months of the LND significantly provoked obesity, hypertension, insulin resistance, and endothelial dysfunction; and 22 months of the LND significantly led to death due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with eNOS down-regulation, adiponectin insufficiency, and gut microbiota dysbiosis.
Conclusions: These results provide the first evidence that long-term dietary NOx deficiency gives rise to MetS, endothelial dysfunction, and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in MetS and its vascular complications. We may have succeeded in identifying specific dietary ingredients that cause MetS even in the absence of excessive calorie intake (Diabetologia 2017).


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