Hydroxyurea-Induced Expression of Glutathione Peroxidase 1 in Red Blood Cells of Individuals with Sickle Cell Anemia

Abstract

Chronic redox imbalance in erythrocytes of individuals with sickle cell disease (SCD) contributes to oxidative stress and likely underlies common etiologies of hemolysis. We measured the amounts of six antioxidant enzymes-SOD1, catalase, glutathione peroxidase 1 (GPx1), as well as peroxiredoxins (Prxs) I, II, and VI-in red blood cells (RBCs) of SCD patients and control subjects. The amounts of SOD1 and Prx VI were reduced by about 17% and 20%, respectively, in SCD RBCs compared with control cells. The amounts of Prx II and GPx1 did not differ between SCD and normal RBCs. However, about 18% of Prx II was inactivated in SCD RBCs as a result of oxidation to sulfinic Prx II, whereas inactive Prx II was virtually undetectable in control cells. Furthermore, GPx1 activity was reduced by about 33% in SCD RBCs, and the loss of activity was correlated with hemolysis in SCD patients. RBCs from SCD patients taking hydroxyurea demonstrated 90% higher GPx1 activity than did those from untreated SCD patients, with no differences seen for the other catalytic antioxidants. Hydroxyurea induced GPx1 expression in multiple cultured cell lines in a manner dependent on both p53 and NO-cGMP signaling pathways. GPx1 expression represents a previously unrecognized potential benefit of hydroxyurea treatment in SCD patients. Antioxid. Redox Signal. 13, 1-11.

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

“…(2) Other reported mechanisms of its action include the reduction of reactive oxygen species (ROS) through increased nitric oxide(3) and selenium dependent Gpx-1 activity. (4)…”

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

“…44 In a phase 2 clinical trial of N-acetylcysteine in SCD patients, administration of the drug decreased the percentage of dense cells, normalized RBC glutathione levels, and decreased the frequency of vaso-occlusive crises. 45 One of the multiple beneficial mechanisms of hydroxyurea in SCD may be reduction of systemic oxidative stress in humans, 46,47 and there is an inverse correlation between hemoglobin F levels and markers of systemic oxidative stress in an SCD mouse model. 48 Trials of antioxidant agents in mouse models of SCD also appear to reduce markers of acute and chronic inflammation.…”

Nitration Transforms a Sensitive Peroxiredoxin 2 into a More Active and Robust Peroxidase

“…Prx2, the most abundant peroxidase in mammalian erythrocytes (17,18), is capable of reducing hydroperoxides as well as peroxynitrite, 5 a potent oxidant formed in vivo by the diffusioncontrolled reaction between superoxide and nitric oxide. Our group recently demonstrated that erythrocyte Prx2 not only is susceptible to overoxidation by peroxynitrite, but it can also get nitrated during catalysis (19).…”