Recent insights into nitrite signaling processes in blood

Helms, Christine; Liu, Xiaohua; Kim‐Shapiro, Daniel B.

doi:10.1515/hsz-2016-0263

Cited by 18 publications

(18 citation statements)

References 95 publications

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“…These include deoxyhaemoglobin, deoxymyoglobin, xanthine oxidoreductase (XOR), mitochondrial complexes and liver cytochromes (see ref. ). The complex redox‐dependent chemistry related to nitrite reduction poses a problem in pinpointing exactly which nitrogen intermediate that mediates the physiological effects investigated.…”

Section: Nitric Oxide Generationmentioning

confidence: 97%

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

2018

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Nitric oxide (NO) importantly contributes to cardiovascular homeostasis by regulating blood flow and maintaining endothelial integrity. Conversely, reduced NO bioavailability is a central feature during natural ageing and in many cardiovascular disorders, including hypertension. The inorganic anions nitrate and nitrite are endogenously formed after oxidation of NO synthase (NOS)-derived NO and are also present in our daily diet. Knowledge accumulated over the past two decades has demonstrated that these anions can be recycled back to NO and other bioactive nitrogen oxides via serial reductions that involve oral commensal bacteria and various enzymatic systems. Intake of inorganic nitrate, which is predominantly found in green leafy vegetables and beets, has a variety of favourable cardiovascular effects. As hypertension is a major risk factor of morbidity and mortality worldwide, much attention has been paid to the blood pressure reducing effect of inorganic nitrate. Here, we describe how dietary nitrate, via stimulation of the nitrate-nitrite-NO pathway, affects various organ systems and discuss underlying mechanisms that may contribute to the observed blood pressure-lowering effect.

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Section: Nitric Oxide Generationmentioning

confidence: 97%

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

2018

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“…Resting plasma nitrite is at least hundreds times more abundant than steady state plasma NO [52], [53] and, preferentially under hypoxia, produces effects characteristic of those attributed to NO through conversion to other NO congeners or NO itself [54]. Unlike other NO donors, nitrite was thought to be ineffective in limiting cytokines associated with circulating blood cell adhesion [55].…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic action of nitrite in sickle cell disease

et al. 2017

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Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.

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“…Once thought to be biologically inert in human physiology [13] , we and others proposed that nitrite serves as a storage pool for nitric oxide that is harnessed under hypoxic conditions. We and others proposed a new function of deoxygenated hemoglobin that targets NO delivery to hypoxic areas where it is needed the most [14] , [15] . The reduction of nitrite to NO by deoxygenated, ferrous hemoglobin is well-known and illustrated in Eq.…”

Section: Introductionmentioning

confidence: 99%

Erythrocytic bioactivation of nitrite and its potentiation by far-red light

et al. 2019

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BackgroundNitrite is reduced by heme-proteins and molybdenum-containing enzymes to form the important signaling molecule nitric oxide (NO), mediating NO signaling. Substantial evidence suggests that deoxygenated hemoglobin within red blood cells (RBCs) is the main erythrocytic protein responsible for mediating nitrite-dependent NO signaling. In other work, infrared and far red light have been shown to have therapeutic potential that some attribute to production of NO. Here we explore whether a combination of nitrite and far red light treatment has an additive effect in NO-dependent processes, and whether this effect is mediated by RBCs.Methods and resultsUsing photoacoustic imaging in a rat model as a function of varying inspired oxygen, we found that far red light (660 nm, five min. exposure) and nitrite feeding (three weeks in drinking water at 100 mg/L) each separately increased tissue oxygenation and vessel diameter, and the combined treatment was additive. We also employed inhibition of human platelet activation measured by flow cytometry to assess RBC-dependent nitrite bioactivation and found that far red light dramatically potentiates platelet inhibition by nitrite. Blocking RBC-surface thiols abrogated these effects of nitrite and far-red light. RBC-dependent production of NO was also shown to be enhanced by far red light using a chemiluminescence-based nitric oxide analyzer. In addition, RBC-dependent bioactivation of nitrite led to prolonged lag times for clotting in platelet poor plasma that was enhanced by exposure to far red light.ConclusionsOur results suggest that nitrite leads to the formation of a photolabile RBC surface thiol-bound species such as an S-nitrosothiol or heme-nitrosyl (NO-bound heme) for which far red light enhances NO signaling. These findings expand our understanding of RBC-mediated NO production from nitrite. This pathway of NO production may have therapeutic potential in several applications including thrombosis, and, thus, warrants further study.

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Recent insights into nitrite signaling processes in blood

Cited by 18 publications

References 95 publications

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

Potential therapeutic action of nitrite in sickle cell disease

Erythrocytic bioactivation of nitrite and its potentiation by far-red light

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