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

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Date
2019-07
Authors
MacKinney, Anson
Woska, Emily
Spasojevic, Ivan
Batinic-Haberle, Ines
Zennadi, Rahima
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Abstract
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.
Type
Journal article
Subject
Erythrocytes
Endothelial Cells
Humans
Vascular Diseases
Anemia, Sickle Cell
Oxygen
Reactive Oxygen Species
Extracellular Signal-Regulated MAP Kinases
Cell Adhesion Molecules
Cell Adhesion
Signal Transduction
Cell Hypoxia
Enzyme Activation
Nitrosation
G-Protein-Coupled Receptor Kinase 2
Feedback, Physiological
NADPH Oxidases
Permalink
https://hdl.handle.net/10161/22408
Published Version (Please cite this version)
10.1016/j.redox.2019.101097
Publication Info
MacKinney, Anson; Woska, Emily; Spasojevic, Ivan; Batinic-Haberle, Ines; & Zennadi, Rahima (2019). Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion. Redox biology, 25. pp. 101097. 10.1016/j.redox.2019.101097. Retrieved from https://hdl.handle.net/10161/22408.
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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Scholars@Duke

Batinic-Haberle

Ines Batinic-Haberle

Professor Emeritus of Radiation Oncology
            A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitu
Zennadi

Rahima Zennadi

Associate Professor in Medicine
Sickle Cell Disease My research investigations in Hematology address the disorders associated with abnormalities affecting cell membrane proteins involved in cell-cell interactions and their role in sickle cell vasculopathy. In sickle cell disease (SCD), recurrent obstruction of the microvasculature leads to serious life-threatening complications such as acute pain crises, acute chest syndrome, kidney failure and cerebrovascular accidents triggered by ischemic injury
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