Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice (original) (raw)
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Free Radical Biology and Medicine, 2008
Endothelial production of nitric oxide (NO) is critical for vascular homeostasis. Nitrite and nitrate are formed endogenously by the step wise oxidation of NO and have for years been regarded as inactive degradation products. As a result both anions are routinely used as surrogate markers of NO production with nitrite as a more sensitive marker. However, both nitrite and nitrate are derived from dietary sources. We sought to determine how exogenous nitrite affects steady state concentrations of NO metabolites thought to originate from NOS derived NO as well as blood pressure and myocardial ischemia-reperfusion (I/R) injury. Mice deficient in endothelial nitric oxide synthase (eNOS −/− ) demonstrated decreased blood and tissue nitrite, nitrate and nitroso which were further reduced by low nitrite (NOx) diet for 1 week. Nitrite supplementation (50mg/L) in the drinking water for 1 week restored NO homeostasis in eNOS −/− mice and protected against I/R injury. Nitrite failed to alter heart rate or mean arterial blood pressure at the protective dose. These data demonstrate the significant influence of dietary nitrite intake on the maintenance of steady-state NO levels. Dietary nitrite and nitrate may serve as essentials nutrient for optimal cardiovascular health and may provide a novel prevention/treatment modality for disease associated with NO insufficiency.
European Journal of Nutrition
Background and aims Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE−/− mouse model. However most patients do not present clinically until well after the disease is established. The aims of this study were to determine whether chronic dietary nitrate supplementation can prevent or reverse the progression of atherosclerosis after disease is already established, as well as to explore the underlying mechanism of these cardiovascular protective effects. Methods 60 apoE−/− mice were given a high fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis. The mice were then randomized to (i) control group (HFD + 1 mmol/kg/day NaCl), (ii) moderate-dose group (HFD +1 mmol/kg/day NaNO3),...
Journal of Clinical Biochemistry and Nutrition
To gain a better understanding of how nitrate may affect carbo hydrate and lipid metabolism, female wild type mice were fed a high fat, high fructose diet supplemented with either 0, 400, or 800 mg nitrate/kg diet for 28 days. Additionally, obese female db/db mice were fed a 5% fat diet supplemented with the same levels and source of nitrate. Nitrate decreased the sodium dependent uptake of glucose by ileal mucosa in wild type mice. Moreover, nitrate significantly decreased triglyceride content and mRNA expression levels of Pparγ in liver and Glut4 in skeletal muscle. Oral glucose tolerance as well as plasma cholesterol, triglyceride, insulin, leptin, glucose and the activity of ALT did not significantly differ between experimental groups but was higher in db/db mice than in wild type mice. Nitrate changed liver fatty acid composition and mRNA levels of Fads only slightly. Further hepatic genes encoding proteins involved in lipid and carbo hydrate metabolism were not significantly different between the three groups. Biomarkers of inflammation and autophagy in the liver were not affected by the different dietary treatments. Overall, the present data suggest that short term dietary supplementation with inorganic nitrate has only modest effects on carbohydrate and lipid metabolism in genetic and dietary induced mouse models of obesity.
Diabetes, 2020
An aging global population combined with sedentary lifestyles and unhealthy diets has contributed to an increasing incidence of obesity and type 2 diabetes. These metabolic disorders are associated with perturbations to nitric oxide (NO) signaling and impaired glucose metabolism. Dietary inorganic nitrate, found in high concentration in green leafy vegetables, can be converted to NO in vivo and demonstrates antidiabetic and antiobesity properties in rodents. Alongside tissues including skeletal muscle and liver, white adipose tissue is also an important physiological site of glucose disposal. However, the distinct molecular mechanisms governing the effect of nitrate on adipose tissue glucose metabolism and the contribution of this tissue to the glucose-tolerant phenotype remain to be determined. Using a metabolomic and stable-isotope labeling approach, combined with transcriptional analysis, we found that nitrate increases glucose uptake and oxidative catabolism in primary adipocyte...
Antioxidants & Redox Signaling, 2012
Mice lacking all three nitric oxide synthase (NOS) genes remain viable even though deletion of the major downstream target of NO, soluble guanylyl cyclase, is associated with a dramatically shortened life expectancy. Moreover, findings of relatively normal flow responses in eNOS knockouts are generally attributed to compensatory mechanisms including upregulation of remaining NOS isoforms, but the alternative possibility that dietary nitrite/nitrate (NOx) may contribute to basal levels of NO signaling has never been investigated. Aim:
A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
Nature Chemical Biology, 2008
Inorganic nitrite (NO 2 -) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO 3 -) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
Effects of long-term dietary nitrate supplementation in mice
Redox Biology, 2015
Background: Inorganic nitrate (NO 3 − ) is a precursor of nitric oxide (NO) in the body and a large number of short-term studies with dietary nitrate supplementation in animals and humans show beneficial effects on cardiovascular health, exercise efficiency, host defense and ischemia reperfusion injury. In contrast, there is a long withstanding concern regarding the putative adverse effects of chronic nitrate exposure related to cancer and adverse hormonal effects. To address these concerns we performed in mice, a physiological and biochemical multi-analysis on the effects of long-term dietary nitrate supplementation. Design: 7 week-old C57BL/6 mice were put on a low-nitrate chow and at 20 weeks-old were treated with NaNO 3 (1 mmol/L) or NaCl (1 mmol/L, control) in the drinking water. The groups were monitored for weight gain, food and water consumption, blood pressure, glucose metabolism, body composition and oxygen consumption until one group was reduced to eight animals due to death or illness. At that point remaining animals were sacrificed and blood and tissues were analyzed with respect to metabolism, cardiovascular function, inflammation, and oxidative stress. Results: Animals were supplemented for 17 months before final sacrifice. Body composition, oxygen consumption, blood pressure, glucose tolerance were measured during the experiment, and vascular reactivity and muscle mitochondrial efficiency measured at the end of the experiment with no differences identified between groups. Nitrate supplementation was associated with improved insulin response, decreased plasma IL-10 and a trend towards improved survival. Conclusions: Long term dietary nitrate in mice, at levels similar to the upper intake range in the western society, is not detrimental.