Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction

Abstract

The nitrite anion is an endogenous product of mammalian nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants, and a constituent of many foods. Research over the past 6 years has revealed surprising biological and cytoprotective activity of this anion. Hypercholesterolemia causes a proinflammatory phenotype in the microcirculation. This phenotype appears to result from a decline in NO bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide, or both. Since nitrite has been shown to be potently cytoprotective and restore NO biochemical homeostasis, we investigated if supplemental nitrite could attenuate microvascular inflammation caused by a high cholesterol diet. C57Bl/6J mice were fed either a normal diet or a high cholesterol diet for 3 wk to induce microvascular inflammation. Mice on the high cholesterol diet received either nitrite-free drinking water or supplemental nitrite at 33 or 99 mg/l ad libitum in their drinking water. The results from this investigation reveal that mice fed a cholesterol-enriched diet exhibited significantly elevated leukocyte adhesion to and emigration through the venular endothelium as well as impaired endothelium-dependent relaxation in arterioles. Administration of nitrite in the drinking water inhibited the leukocyte adhesion and emigration and prevented the arteriolar dysfunction. This was associated with sparing of reduced tetrahydrobiopterin and decreased levels of C-reactive protein. These data reveal novel anti-inflammatory properties of nitrite and implicate the use of nitrite as a new natural therapy for microvascular inflammation and endothelial dysfunction associated with hypercholesterolemia.

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

“…Following chronic treatment with KNO 3 , a reduced leukocyte rolling and adherence was evident in ApoE KO mice, a finding in agreement with previous observations demonstrating reductions in leukocyte rolling in response to dietary nitrite in WT mice fed a HFD (16). Interestingly, however, the beneficial effects of inorganic nitrate were only evident in mice fed a NCD and not in HFD-fed animals.…”

“…This nitrite-rich saliva is then swallowed and enters the blood, where it can be further reduced to NO by vascular nitrite reductases, including xanthine oxidoreductase (XOR) (13,14). Recent evidence suggests that dietary nitrate pretreatment or acute nitrite administration, by delivering NO to the vasculature, reduces leukocyte activation in response to an acute chemokineinduced inflammation (15) or following prolonged cholesterol treatment (16). Because recruitment and activation of leukocytes is a pivotal process in both plaque initiation and progression, we investigated whether dietary nitrate might reduce atherosclerosis through targeting of inflammatory mechanisms in athero-prone Apolipoprotein (Apo)E knockout (KO) mice.…”

Nitrate and Nitrite Content of Human, Formula, Bovine, and Soy Milks: Implications for Dietary Nitrite and Nitrate Recommendations

“…15,16 In animal models, nitrite has been demonstrated to enhance mucosal blood flow and serve antimicrobial functions, 17 protect against heart attack 18 and stroke, 19 and reverse vascular inflammation from a high fat diet. 20 Gastroprotective and blood pressure-lowering effects of dietary nitrate are abolished by frequent spitting after nitrate consumption or by antiseptic mouthwash. 13,21 These manipulations abolish the reduction of nitrate to nitrite by bacteria on the lingual surface made possible by enterosalivary circulation of nitrate.…”

Quantitative and Comparative Contents of Nitrate and Nitrite in Beta vulgaris L. by Reversed-Phase High-Performance Liquid Chromatography-Fluorescence

“…Thus, it is plausible that a more intensive usage of such fertilizers may explain the higher NO 3 − and NO 2 − content from the USA when compared to beetroots from Brazil. Recently, several intervention studies have been conducted using different amounts of beetroot (in juice form) for investigating the contribution of NO 3 − in NO synthesis (Webb et al 2008;Bailey et al 2009;Stokes et al 2009;Kapil et al 2010;Vanhatalo et al 2011;Murphy et al 2012;Wylie et al 2013 . However, no information about how this content was evaluated was provided.…”

“…In addition, the vegetable is also considered a dietary NO 3 − source (Pennington 1998;Santamaría 2006;Tamme et al 2006). The NO 3 − content in this food matrix has been proposed to enhance blood perfusion (Webb et al 2008;Kapil et al 2010), restore endothelial function (Stokes et al 2009), and improve exercise performance Murphy et al 2012). These properties may be explained by the possible effect of NO 3 − present in beetroot juice in stimulating the endogenous synthesis of nitric oxide (NO).…”