Disrupting the vicious cycle created by NOX activation in sickle erythrocytes exposed to hypoxia/reoxygenation prevents adhesion and vasoocclusion.
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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.
Anemia, Sickle Cell
Reactive Oxygen Species
Extracellular Signal-Regulated MAP Kinases
Cell Adhesion Molecules
G-Protein-Coupled Receptor Kinase 2
Published Version (Please cite this version)10.1016/j.redox.2019.101097
Publication InfoMacKinney, 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.
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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
Associate Professor in Medicine
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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