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Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice.
Karolinska Institutet.
Karolinska Institutet.ORCID iD: 0000-0002-1343-8656
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2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 41, 17716-20 p.Article in journal (Refereed) Published
Abstract [en]

The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate-nitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.

Place, publisher, year, edition, pages
2010. Vol. 107, no 41, 17716-20 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:gih:diva-2080DOI: 10.1073/pnas.1008872107PubMedID: 20876122OAI: oai:DiVA.org:gih-2080DiVA: diva2:474309
Available from: 2012-01-09 Created: 2012-01-09 Last updated: 2016-08-08Bibliographically approved
In thesis
1. Dietary inorganic nitrate: role in exercise physiology, cardiovascular and metabolic regulation
Open this publication in new window or tab >>Dietary inorganic nitrate: role in exercise physiology, cardiovascular and metabolic regulation
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nitric oxide (NO) is a ubiquitous signaling molecule with a vast number of tasks in the body, including regulation of cardiovascular and metabolic function. A decreased bioavailability of NO is a central event in disorders such as hypertension and metabolic syndrome. NO is also important in the regulation of blood flow and metabolism during exercise. The production of NO has previously been thought to be under the exclusive control of the nitric oxide synthases (NOS) but this view is now being seriously challenged. Recent lines of research suggest the existence of an NO-synthase independent pathway in which the supposedly inert NO oxidation products nitrate (NO3-) and nitrite (NO2-) can be reduced back to NO in blood and tissues. An important additional source of nitrate is our everyday diet and certain vegetables are particularly rich in this anion. In this thesis the possibility that dietary derived nitrate is metabolized in vivo to form reactive nitrogen oxides with NO-like bioactivity has been explored. It is shown that nitrate in amounts easily achieved via the diet, increases the systemic levels of nitrite and reduces blood pressure in healthy humans. Moreover, nitrate reduces whole body oxygen cost during submaximal and maximal exercise; a surprising effect involving improvement in mitochondrial efficiency and reduced expression of specific mitochondrial proteins regulating proton conductance. Alterations in the mitochondrial affinity for oxygen can explain this reduction in both submaximal and maximal oxygen consumption and predicts basal metabolic rate in humans. Finally, in mice lacking endothelial NO synthase, dietary supplementation with nitrate could reverse several features of the metabolic syndrome that develop in these animals. These studies demonstrate that dietary nitrate can fuel a nitrate-nitrite-NO pathway with important implications for cardiovascular and metabolic functions in health and disease.

Place, publisher, year, edition, pages
Solna: Karolinska Institutet, 2011
National Category
Medical and Health Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-2079 (URN)978-91-7457-397-8 (ISBN)
Public defence
2011-06-17, Aulan Farmakologen, Nanna Svartz väg 2, Solna, 09:00 (English)
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Note
Avhandling vid Karolinska Institutet och Gymnastik- och idrottshögskolan, GIHAvailable from: 2012-01-09 Created: 2012-01-09 Last updated: 2016-08-08Bibliographically approved

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