title: Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.|Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kina-Tanada
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Sakanashi
authors.affiliation: Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kaname
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Nakasone
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Chisayo
authors.initials: C
authors.lastname: Kozuka
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.|Regenerative Medicine Research Center, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Haruaki
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taira
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Totsuka
authors.affiliation: Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Kina
authors.affiliation: Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sunakawa
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.affiliation: Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.affiliation: Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Third Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohya
authors.affiliation: Department of Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.affiliation: Department of Oral and Maxillofacial Functional Rehabilitation, University of the Ryukyus, Okinawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Arasaki
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan. tsutsui@med.u-ryukyu.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism*
chemical_list: D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide
keywords: Acute myocardial infarction; Cardiovascular death; Diet; Endothelial dysfunction; Metabolic syndrome; Mice; Nitrate; Nitric oxide; Nitrite