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.

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Published Version (Please cite this version)

10.1182/bloodadvances.2019031633

Publication Info

McMahon, Timothy J, Siqing Shan, Daniel A Riccio, Milena Batchvarova, Hongmei Zhu, Marilyn J Telen and Rahima Zennadi (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.

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Scholars@Duke

Telen

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 research focuses especially on adhesion receptors. The goals of this work are (1) to understand the mechanism and role of red cell adhesion to leukocytes and endothelium in sickle cell disease; (2) to understand the signaling mechanisms leading to activation (and inactivation) of red cell adhesion molecules; (3) to understand the molecular basis of blood group antigen expression, and (4) to understand the interactions of erythroid membrane proteins with other cells and with extracellular matrix..

Recent investigations have focused on the role of signaling pathways in the upregulation of sickle red cell adhesion. Present studies include (1) investigation of beta-adrenergic signaling pathway responsible for activation of B-CAM/LU and LW adhesion receptors; (2) understanding how nitric oxide and ATP downregulate sickle red cell adhesion; (3) studying the effect of these processes in animal models.

Dr. Telen is also involved in a large multicenter study looking for genetic polymorphisms that affect clinical outcomes in sickle cell disease, as well as a multi-center study investigating the mechanisms and treatment of pulmonary hypertension in sickle cell disease.


Key Words:

Adhesion molecules
Erythrocyte membrane
Sickle cell disease
Transfusion medicine
Immunohematology
CD44
B-CAM/LU
Genetic polymorphisms


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