Nitroprusside inhibits calcium‐induced impairment of red blood cell deformability

Barodka, Viachaslau; Mohanty, Joy G.; Mustafa, Asif K.; Santhanam, Lakshmi; Nyhan, Aoibhinn; Bhunia, Anil K.; Sikka, Gautam; Nyhan, Daniel; Berkowitz, Dan E.; Rifkind, Joseph M.

doi:10.1111/trf.12291

Cited by 45 publications

(59 citation statements)

References 45 publications

(78 reference statements)

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“…In addition, calcium leak leads to membrane lipid asymmetry with exposure of phosphatidylserine on the surface of RBCs which contributes to increased adhesivity of sickle RBCs [70], [71]. These same phenomena can be recapitulated in normal RBCs using calcium ionophores [66], [70], [72]. Thus, inhibiting the Gardos channel has been a major therapeutic target in treating SCD as it would improve RBC deformability, decrease RBC adhesion, and decrease sickling [73].…”

Section: Resultsmentioning

confidence: 99%

“…A recent study using inhaled NO showed promise in reducing pain crises [95], but the study was small. Despite potential of NO to relieve multiple symptoms of SCD (as demonstrated by us and others [36], [37], [38], [39], [40], [42], [66], [72], [88]), successful translation has been elusive. However, it is important to note that not all NO congeners are the same and nitrite has several properties that make it more promising than other agents: (1) nitrite targets NO activity to hypoxic areas where it is most needed [88] (unlike other agents like NO inhalation that targets the lungs and sGC activators which have systemic activity), (2) nitrite can be delivered to produce NO activity chronically with potential for constantly elevated levels achieved through the nitrate-nitrite-NO cycle [74].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Potential therapeutic action of nitrite in sickle cell disease

et al. 2017

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“…During storage, erythrocyte membrane permeability to calcium (Ca 2+ ) ions increases over time, leading to increased intracellular Ca 2+ levels. Intracellular Ca 2+ activates calcium-sensitive KCa3.1 ion channels, which are located in the erythrocyte membrane 35 . The resulting potassium ion efflux causes RBCs to shrink and makes their cell membranes less flexible 36 .…”

Section: Discussionmentioning

confidence: 99%

“…The resulting potassium ion efflux causes RBCs to shrink and makes their cell membranes less flexible 36 . Previous studies showed that nitric oxide has a crucial role in enhancing RBC deformability and that reduced RBC nitric oxide levels decrease deformability 35,37 . Loss of RBC deformability may lead to an increased rate of intravascular hemolysis and a reduced lifespan of transfused stored RBCs.…”

Section: Discussionmentioning

confidence: 99%

Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension

Muenster

Beloiartsev

et al. 2016

Anesthesiology

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Background Transfusion of packed erythrocytes stored for a long duration is associated with increased pulmonary arterial pressure and vascular resistance. Prolonged storage decreases erythrocyte deformability, and older erythrocytes are rapidly removed from the circulation after transfusion. The authors studied whether treating stored packed ovine erythrocytes with NO before transfusion could prevent pulmonary vasoconstriction, enhance erythrocyte deformability, and prolong erythrocyte survival after transfusion. Methods Ovine leukoreduced packed erythrocytes were treated before transfusion with either NO gas or a short-lived NO donor. Sheep were transfused with autologous packed erythrocytes, which were stored at 4°C for either 2 (“fresh blood”) or 40 days (“stored blood”). Pulmonary and systemic hemodynamic parameters were monitored before, during, and after transfusion. Transfused erythrocytes were labeled with biotin to measure their circulating lifespan. Erythrocyte deformability was assessed before and after NO treatment using a microfluidic device. Results NO treatment improved the deformability of stored erythrocytes and increased the number of stored erythrocytes circulating at 1 and 24 h after transfusion. NO treatment prevented transfusion-associated pulmonary hypertension (mean pulmonary arterial pressure at 30 min of 21 ± 1 vs. 15 ± 1 mmHg in control and NO–treated packed erythrocytes, P < 0.0001). Washing stored packed erythrocytes before transfusion did not prevent pulmonary hypertension. Conclusions NO treatment of stored packed erythrocytes before transfusion oxidizes cell-free oxyhemoglobin to methemoglobin, prevents subsequent NO scavenging in the pulmonary vasculature, and limits pulmonary hypertension. NO treatment increases erythrocyte deformability and erythrocyte survival after transfusion. NO treatment might provide a promising therapeutic approach to prevent pulmonary hypertension and extend erythrocyte survival.

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“…Enhanced intracellular calcium has several effects that can affect deformability. This includes activation of the Gardos channel resulting in leakage of potassium from the RBC affecting cation homeostasis (Ney et al, 1990; Barodka et al, 2013a) causing shrinkage of the cell and impaired deformability. Calcium also activates calpain that can degrade additional proteins on the membrane (Redding et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging

2014

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Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Decreased deformability of RBCs is, therefore, one of the factors that can contribute to the elimination of aged or damaged RBCs from the circulation. This process can also cause impaired oxygen delivery, which contributes to the pathology of a number of diseases. Studies from our laboratory have shown that oxidative stress plays a significant role in damaging the RBC membrane and impairing its deformability. RBCs are continuously exposed to both endogenous and exogenous sources of reactive oxygen species (ROS) like superoxide and hydrogen peroxide (H2O2). The bulk of the ROS are neutralized by the RBC antioxidant system consisting of both non-enzymatic and enzymatic antioxidants including catalase, glutathione peroxidase and peroxiredoxin-2. However, the autoxidation of hemoglobin (Hb) bound to the membrane is relatively inaccessible to the predominantly cytosolic RBC antioxidant system. This inaccessibility becomes more pronounced under hypoxic conditions when Hb is partially oxygenated, resulting in an increased rate of autoxidation and increased affinity for the RBC membrane. We have shown that a fraction of peroxyredoxin-2 present on the RBC membrane may play a major role in neutralizing these ROS. H2O2 that is not neutralized by the RBC antioxidant system can react with the heme producing fluorescent heme degradation products (HDPs). We have used the level of these HDP as a measure of RBC oxidative Stress. Increased levels of HDP are detected during cellular aging and various diseases. The negative correlation (p < 0.0001) between the level of HDP and RBC deformability establishes a contribution of RBC oxidative stress to impaired deformability and cellular stiffness. While decreased deformability contributes to the removal of RBCs from the circulation, oxidative stress also contributes to the uptake of RBCs by macrophages, which plays a major role in the removal of RBCs from circulation. The contribution of oxidative stress to the removal of RBCs by macrophages involves caspase-3 activation, which requires oxidative stress. RBC oxidative stress, therefore, plays a significant role in inducing RBC aging.

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Nitroprusside inhibits calcium‐induced impairment of red blood cell deformability

Abstract: Our results suggest that nitroprusside treatment of RBCs may protect them from intracellular calcium increase-mediated stiffness, which may occur during microvascular perfusion in diseased states, as well as during RBC storage.

Cited by 45 publications

References 45 publications

Potential therapeutic action of nitrite in sickle cell disease

Potential therapeutic action of nitrite in sickle cell disease

Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension

Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging

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