Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- McMahon, TJ; Shan, S; Riccio, DA; Batchvarova, M; Zhu, H; Telen, MJ; Zennadi, R
Published Date
- September 10, 2019
Published In
- Blood Adv
Volume / Issue
- 3 / 17
Start / End Page
- 2586 - 2597
PubMed ID
- 31484636
Pubmed Central ID
- 31484636
Electronic International Standard Serial Number (EISSN)
- 2473-9537
Digital Object Identifier (DOI)
- 10.1182/bloodadvances.2019031633
Language
- eng
Conference Location
- United States