Potential therapeutic action of nitrite in sickle cell disease

Wajih, Nadeem; Basu, Swati; Jailwala, Anuj; Kim, Hee Won; Ostrowski, David Alfred; Perlegas, Andreas; Bolden, Crystal; Buechler, Nancy L.; Gladwin, Mark T.; Caudell, David L.; Rahbar, Elaheh; Alexander-Miller, Martha A.; Vachharajani, Vidula; Kim‐Shapiro, Daniel B.

doi:10.1016/j.redox.2017.05.006

Cited by 31 publications

(33 citation statements)

References 90 publications

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“…Hemoglobin acts as a sink that is able to store nitric oxide equivalents, whether it is nitrite or S‐nitrosylated proteins, for use in remote areas of the vasculature and can convert nitrite to NO under low oxygen conditions . Regional nitric oxide release inhibits platelet activation and aggregation, and could impact resting and hyperemic blood flow . Some data implicate mechanical stress and RBC deformation as stimuli for local NO .…”

Section: Discussionmentioning

confidence: 99%

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

et al. 2019

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We have previously demonstrated that sickle cell disease (SCD) patients maintain normal global systemic and cerebral oxygen delivery by increasing cardiac output. However, ischemic end‐organ injury remains common suggesting that tissue oxygen delivery may be impaired by microvascular dysregulation or damage. To test this hypothesis, we performed fingertip laser Doppler flowmetry measurements at the base of the nailbed and regional oxygen saturation (rSO2) on the dorsal surface of the same hand. This was done during flow mediated dilation (FMD) studies in 26 chronically transfused SCD, 75 non‐transfused SCD, and 18 control subjects. Chronically transfused SCD patients were studied prior to and following a single transfusion and there was no acute change in rSO2 or perfusion. Laser Doppler estimates of resting perfusion were 76% higher in non‐transfused and 110% higher in transfused SCD patients, compared to control subjects. In contrast, rSO2 was 12 saturation points lower in non‐transfused SCD patients, but normal in the transfused SCD patients. During cuff occlusion, rSO2 declined at the same rate in all subjects suggesting similar intrinsic oxygen consumption rates. Upon cuff release, laser doppler post occlusive hyperemia was blunted in SCD patients in proportion to their resting perfusion values. Transfusion therapy did not improve the hyperemia response. FMD was impaired in SCD subjects but partially ameliorated in transfused SCD subjects. Taken together, non‐transfused SCD subjects demonstrate impaired conduit artery FMD, impaired microcirculatory post‐occlusive hyperemia, and resting hypoxia in the hand despite compensated oxygen delivery, suggesting impaired oxygen supply‐demand matching. Transfusion improves FMD and oxygen supply‐demand matching but not microcirculation hyperemic response.

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Section: Discussionmentioning

confidence: 99%

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

et al. 2019

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“…Nitric oxide inhibits leukocyte adhesion and platelet adhesion and activation, thus blunting hemolysis and thromboinflammation associated with SCD. 10,101 Several agents that target different aspects of oxidant and nitric oxide biology have been used to modify SCD and reduce VOC events ( Table 1). Some of the particular interest are as follows.…”

Section: Antiplatelet and Anticoagulantsmentioning

confidence: 99%

“…However, in adults with SCD and mild to moderate ACS, nitric oxide therapy failed to show any reduction in treatment, suggesting that nitric oxide therapy is complex and requires further understanding. 64 The failure of inhaled nitric oxide may be because it mainly targets the lungs and was used under acute care settings, which may have been insufficient for I/RI affected tissues 101 with less systemic action.…”

Section: Nitrite Therapymentioning

confidence: 99%

Ischemia-Reperfusion Injury in Sickle Cell Disease

Ansari

Gavins

2019

The American Journal of Pathology

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Sickle cell disease (SCD) is one of the most common hereditary hemoglobinopathies worldwide, affecting almost 400,000 newborns globally each year. It is characterized by chronic hemolytic anemia and endothelial dysfunction, resulting in a constant state of disruption of the vascular system and leading to recurrent episodes of ischemia-reperfusion injury (I/RI) to multiple organ systems. I/RI is a fundamental vascular pathobiological paradigm and contributes to morbidity and mortality in a wide range of conditions, including myocardial infarction, stroke, acute kidney injury, and transplantation. I/RI is characterized by an initial restriction of blood supply to an organ, which can lead to ischemia, followed by the subsequent restoration of perfusion and concomitant reoxygenation. Recent advances in the pathophysiology of SCD have led to an understanding that many of the consequences of this disease can be explained by mechanisms associated with I/RI. The following review focuses on the evolving pathobiology of SCD, how various complications of SCD can be attributed to I/RI, and the role of timely therapeutic intervention(s) based on targeting mediators or pathways that influence I/R insult. (Am J Pathol 2019, 189: 706e718; https://doi.

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“…123 In vitro studies and in vivo studies with transgenic SCD mice have shown that nitrite may also improve RBC deformability as well as reduce RBC, leukocyte, and platelet adhesion, in addition to reducing hemolysis. 93 When administered to a small number of individuals with SCD and in steady state, sodium nitrite infusions augmented plasma nitrite concentrations and augmented forearm blood flow without causing hypotension or clinically significant methemoglobinemia. 94 Potential for sGC agonist therapy in SCD While decreased NO signaling may play a major role in SCD pathophysiology, restoration of NO-dependent signaling more directly with NO inhalation and L-arginine supplementation in patients has shown limited efficacy, perhaps due to the fact that the mechanisms that limit NO production and bioavailability are sustained even during the therapy.…”

Section: No-based Therapies In Scdmentioning

confidence: 99%

cGMP modulation therapeutics for sickle cell disease

Conran

Torres

2019

Exp Biol Med (Maywood)

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Sickle cell disease (SCD) is an inherited disease caused by the production of abnormal hemoglobin (Hb) S, whose deoxygenation-induced polymerization results in red blood cell (RBC) sickling and numerous pathophysiological consequences. SCD affects approximately 300,000 newborns worldwide each year and is associated with acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. Chronic intravascular hemolysis in SCD significantly reduces vascular nitric oxide (NO) bioavailability, consequently decreasing intracellular signaling via cyclic guanosine monophosphate (cGMP), in turn diminishing vasodilation and contributing to the inflammatory mechanisms that trigger vaso-occlusive processes. Oxidative stress may further reduce NO bioavailability in SCD and can oxidize the intracellular enzyme target of NO, soluble guanylate cyclase (sGC), rendering it inactive. Increasing intracellular cGMP-dependent signaling constitutes an important pharmacological therapeutic approach for SCD with a view to augmenting vasodilation, and reducing inflammatory mechanisms, as well as for increasing the production of anti-polymerizing fetal Hb in erythroid cells. Pharmacological agents under pre-clinical and clinical investigation for SCD include NO-based therapeutics to augment NO bioavailability, as well as heme-dependent sGC stimulators and heme-independent sGC activators that directly stimulate native and oxidized sGC, respectively, therefore bypassing the need for vascular NO delivery. Additionally, the phosphodiesterases (PDEs) that degrade intracellular cyclic nucleotides with specific cellular distributions are attractive drug targets for SCD; PDE9 is highly expressed in hematopoietic cells, making the use of PDE9 inhibitors, originally developed for use in neurological diseases, a potential approach that could rapidly amplify intracellular cGMP concentrations in a relatively tissue-specific manner. Impact statement Sickle cell disease (SCD) is one of the most common inherited diseases and is associated with a reduced life expectancy and acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. At present, treatment of SCD is limited to hematopoietic stem cell transplant, transfusion, and limited options for pharmacotherapy, based principally on hydroxyurea therapy. This review highlights the importance of intracellular cGMP-dependent signaling pathways in SCD pathophysiology; modulation of these pathways with soluble guanylate cyclase (sGC) stimulators or phosphodiesterase (PDE) inhibitors could potentially provide vasorelaxation and anti-inflammatory effects, as well as elevate levels of anti-sickling fetal hemoglobin.

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Potential therapeutic action of nitrite in sickle cell disease

Cited by 31 publications

References 90 publications

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

Ischemia-Reperfusion Injury in Sickle Cell Disease

cGMP modulation therapeutics for sickle cell disease

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