Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.

dc.contributor.author

McMahon, Timothy J

dc.contributor.author

Shan, Siqing

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Riccio, Daniel A

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Batchvarova, Milena

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Zhu, Hongmei

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Telen, Marilyn J

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Zennadi, Rahima

dc.date.accessioned

2021-03-01T17:03:23Z

dc.date.available

2021-03-01T17:03:23Z

dc.date.issued

2019-09

dc.date.updated

2021-03-01T17:03:22Z

dc.description.abstract

Sickle red blood cells (SSRBCs) are adherent to the endothelium, activate leukocyte adhesion, and are deficient in bioactive nitric oxide (NO) adducts such as S-nitrosothiols (SNOs), with reduced ability to induce vasodilation in response to hypoxia. All these pathophysiologic characteristics promote vascular occlusion, the hallmark of sickle cell disease (SCD). Loading hypoxic SSRBCs in vitro with NO followed by reoxygenation significantly decreased epinephrine-activated SSRBC adhesion to the endothelium, the ability of activated SSRBCs to mediate leukocyte adhesion in vitro, and vessel obstruction in vivo. Because transfusion is frequently used in SCD, we also determined the effects of banked (SNO-depleted) red blood cells (RBCs) on vaso-occlusion in vivo. Fresh or 14-day-old normal RBCs (AARBCs) reduced epinephrine-activated SSRBC adhesion to the vascular endothelium and prevented vaso-occlusion. In contrast, AARBCs stored for 30 days failed to decrease activated SSRBC adhesivity or vaso-occlusion, unless these RBCs were loaded with NO. Furthermore, NO loading of SSRBCs increased S-nitrosohemoglobin and modulated epinephrine's effect by upregulating phosphorylation of membrane proteins, including pyruvate kinase, E3 ubiquitin ligase, and the cytoskeletal protein 4.1. Thus, abnormal SSRBC NO/SNO content both contributes to the vaso-occlusive pathophysiology of SCD, potentially by affecting at least protein phosphorylation, and is potentially amenable to correction by (S)NO repletion or by RBC transfusion.

dc.identifier

bloodadvances.2019031633

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2473-9529

dc.identifier.issn

2473-9537

dc.identifier.uri

https://hdl.handle.net/10161/22407

dc.language

eng

dc.publisher

American Society of Hematology

dc.relation.ispartof

Blood advances

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10.1182/bloodadvances.2019031633

dc.subject

Endothelium, Vascular

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Erythrocytes

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Humans

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Vascular Diseases

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Anemia, Sickle Cell

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Oxygen

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Nitric Oxide

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Hemoglobins

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Membrane Proteins

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Erythrocyte Transfusion

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Cell Adhesion

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Phosphorylation

dc.title

Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.

dc.type

Journal article

duke.contributor.orcid

McMahon, Timothy J|0000-0002-3404-3223

duke.contributor.orcid

Telen, Marilyn J|0000-0003-3809-1780

pubs.begin-page

2586

pubs.end-page

2597

pubs.issue

17

pubs.organisational-group

School of Medicine

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Duke Cancer Institute

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Duke Global Health Institute

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Pathology

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Medicine, Hematology

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Duke

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Institutes and Centers

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University Institutes and Centers

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Institutes and Provost's Academic Units

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Clinical Science Departments

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Medicine

pubs.organisational-group

Radiation Oncology

pubs.organisational-group

Medicine, Pulmonary, Allergy, and Critical Care Medicine

pubs.publication-status

Published

pubs.volume

3

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