[Redox Biology] Potential therapeutic action of nitrite in sickle cell disease
Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.
Nadeem Wajiha, b, Swati Basua, b, Anuj Jailwalaa, Hee Won Kima, David Ostrowskia, Andreas Perlegasa, Crystal A. Boldena, Nancy L. Buechlerc, Mark T. Gladwind, e, David L. Caudellf, Elaheh Rahbarg, Martha A. Alexander-Millerh, Vidula Vachharajanib, c, , , Daniel B. Kim-Shapiroa, b, , a Department of Physics, Wake Forest University, Winston-Salem, NC 27109, United States b Translational Science Center, Wake Forest University, Winston-Salem, NC 27109, United States c Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States d Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, United States e Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States f Department of Pathology-Comparative Medicine, Section on Rheumatology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States g Department of Biomedical Engineering, Section on Rheumatology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States h Department of Microbiology and Immunology, Section on Rheumatology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States Received 5 April 2017, Revised 7 May 2017, Accepted 8 May 2017, Available online 10 May 2017
Show less https://doi.org/10.1016/j.redox.2017.05.006