Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.
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.
Type
Journal articleSubject
Endothelium, VascularErythrocytes
Humans
Vascular Diseases
Anemia, Sickle Cell
Oxygen
Nitric Oxide
Hemoglobins
Membrane Proteins
Erythrocyte Transfusion
Cell Adhesion
Phosphorylation
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https://hdl.handle.net/10161/22407Published Version (Please cite this version)
10.1182/bloodadvances.2019031633Publication Info
McMahon, Timothy J; Shan, Siqing; Riccio, Daniel A; Batchvarova, Milena; Zhu, Hongmei;
Telen, Marilyn J; & Zennadi, Rahima (2019). Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.
Blood advances, 3(17). pp. 2586-2597. 10.1182/bloodadvances.2019031633. Retrieved from https://hdl.handle.net/10161/22407.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Timothy Joseph McMahon
Professor of Medicine
The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel
roles of the red blood cell (RBC) in the circulation. The regulated release of the
vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle
in mammals optimizes nutrient delivery at multiple levels, especially in the lung
(gas exchange) and the peripheral microcirculation (O2 transport to tissues). Deficiency
of RBC SNO bioactivity (as in human RBCs banked for transfusion),
Siqing Shan
Assistant Professor Emeritus of Radiation Oncology
My researches focus on tumor microenvironment physiology and biology (tumor microcirculation,
oxygenation and liposomal drug pharmacokenetics in microvascular level), especially
the molecular and cellular mechanisms of tumor angiogenesis. In addition to in vitro
and ex vivo assays, we apply different animal models to quantitatively investigate
the effects of novel biological and chemical agents on tumor cellular behaviors and
initiation of early angiogenesis in vivo.
Marilyn Jo Telen
Wellcome Clinical Distinguished Professor of Medicine in Honor of R. Wayne Rundles,
M.D.
Dr. Telen is recognized as an expert in the biochemistry and molecular genetics of
blood group antigens and the pathophysiological mechanisms of vaso-occlusion in sickle
cell disease. She is the Director of the Duke Comprehensive Sickle Cell Center. Dr.
Telen's laboratory focuses on structure/function analysis of membrane proteins expressed
by erythroid cells, as well as the role of these proteins in non-erythroid cells.
Proteins are also studied in transfectant systems, and researc
Rahima Zennadi
Associate Professor in Medicine
My research in Hematology addresses three areas of investigation: disorders associated
with sickle cell disease pathophysiology, venous thrombosis/thromboembolism (VT/E)
associated with aging, and cerebrovascular injury.
In sickle cell disease, vaso-occlusion leads to serious life-threatening complications,
including acute pain crises and irreversible organ damage. Vaso-occlusion is caused
largely by sickle red blood cell adhesion to the vascular endothelium. Prevention
of
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