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Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion.

Publication ,  Journal Article
MacKinney, A; Woska, E; Spasojevic, I; Batinic-Haberle, I; Zennadi, R
Published in: Redox Biol
July 2019

In sickle cell disease (SCD), recurrent painful vasoocclusive crisis are likely caused by repeated episodes of hypoxia and reoxygenation. The sickle erythrocyte (SSRBC) adhesion plays an active role in vasoocclusion. However, the effect of prolonged reoxygenation after hypoxic stress on the molecular mechanisms in SSRBCs involved in onset of episodic vasoocclusion remain unclear. Exposure of human SSRBCs to hypoxia followed by 2 h reoxygenation, increased reactive oxygen species (ROS) production. Using specific pharmacological inhibitors, we show that excess ROS production in both reticulocytes and mature SSRBCs is regulated by NADPH oxidases (NOXs), the mitogen-activated protein kinase (ERK1/2), and G-protein coupled-receptor kinase 2 (GRK2). Consequently, SSRBC ROS create an intracellular positive feedback loop with ERK1/2 and GRK2 to mediate SSRBC adhesion to endothelium in vitro, and vasoocclusion in a mouse model of vasoocclusion in vivo. Importantly, reducing ROS levels in SSRBCs with redox-active manganese (Mn) porphyrins, commonly known as mimics of superoxide dismutase (SOD), disrupted the cycle created by ROS by affecting NOX and GRK2 activities and ERK1/2 phosphorylation, thus abrogating RBC-endothelial interactions. Inhibition adhesion assays show that LW (ICAM-4, CD242) blood group glycoprotein and CD44 are the RBC adhesion molecules mediating endothelial binding. Conversely, hypoxia/reoxygenation of normal RBCs failed to activate this feedback loop, and adhesion. These findings provide novel insights into the pathophysiological significance of the deleterious cycle created by NOX-dependent ROS, GRK2 and ERK1/2 within SSRBCs activated by hypoxia/reoxygenation, and involved in SSRBC adhesion and vasoocclusion. Thus, this loop in SSRBCs, which can be disrupted by Mn porphyrins, likely drives the profound SCD vasculopathy, and may point to new therapeutic targets to prevent chronic vasoocclusive events.

Duke Scholars

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

July 2019

Volume

25

Start / End Page

101097

Location

Netherlands

Related Subject Headings

  • Vascular Diseases
  • Signal Transduction
  • Reactive Oxygen Species
  • Oxygen
  • Nitrosation
  • NADPH Oxidases
  • Humans
  • G-Protein-Coupled Receptor Kinase 2
  • Feedback, Physiological
  • Extracellular Signal-Regulated MAP Kinases
 

Citation

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MLA
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MacKinney, A., Woska, E., Spasojevic, I., Batinic-Haberle, I., & Zennadi, R. (2019). Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion. Redox Biol, 25, 101097. https://doi.org/10.1016/j.redox.2019.101097
MacKinney, Anson, Emily Woska, Ivan Spasojevic, Ines Batinic-Haberle, and Rahima Zennadi. “Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion.Redox Biol 25 (July 2019): 101097. https://doi.org/10.1016/j.redox.2019.101097.
MacKinney A, Woska E, Spasojevic I, Batinic-Haberle I, Zennadi R. Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion. Redox Biol. 2019 Jul;25:101097.
MacKinney, Anson, et al. “Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion.Redox Biol, vol. 25, July 2019, p. 101097. Pubmed, doi:10.1016/j.redox.2019.101097.
MacKinney A, Woska E, Spasojevic I, Batinic-Haberle I, Zennadi R. Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion. Redox Biol. 2019 Jul;25:101097.
Journal cover image

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

July 2019

Volume

25

Start / End Page

101097

Location

Netherlands

Related Subject Headings

  • Vascular Diseases
  • Signal Transduction
  • Reactive Oxygen Species
  • Oxygen
  • Nitrosation
  • NADPH Oxidases
  • Humans
  • G-Protein-Coupled Receptor Kinase 2
  • Feedback, Physiological
  • Extracellular Signal-Regulated MAP Kinases