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Hydroxyurea induces fetal hemoglobin by the nitric oxide–dependent activation of soluble guanylyl cyclase
Vladan P. Cokic, … , Mark T. Gladwin, Alan N. Schechter
Vladan P. Cokic, … , Mark T. Gladwin, Alan N. Schechter
Published January 15, 2003
Citation Information: J Clin Invest. 2003;111(2):231-239. https://doi.org/10.1172/JCI16672.
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Article Aging

Hydroxyurea induces fetal hemoglobin by the nitric oxide–dependent activation of soluble guanylyl cyclase

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Abstract

Hydroxyurea treatment of patients with sickle-cell disease increases fetal hemoglobin (HbF), which reduces hemoglobin S polymerization and clinical complications. Despite its use in the treatment of myeloproliferative diseases for over 30 years, its mechanism of action remains uncertain. Recent studies have demonstrated that hydroxyurea generates the nitric oxide (NO) radical in vivo, and we therefore hypothesized that NO-donor properties might determine the hemoglobin phenotype. We treated both K562 erythroleukemic cells and human erythroid progenitor cells with S-nitrosocysteine (CysNO), an NO donor, and found similar dose- and time-dependent induction of γ-globin mRNA and HbF protein as we observed with hydroxyurea. Both hydroxyurea and CysNO increased cGMP levels, and the guanylyl cyclase inhibitors ODQ, NS 2028, and LY 83,538 abolished both the hydroxyurea- and CysNO-induced γ-globin expression. These data provide strong evidence for an NO-derived mechanism for HbF induction by hydroxyurea and suggest possibilities for therapies based on NO-releasing or -potentiating agents.

Authors

Vladan P. Cokic, Reginald D. Smith, Bojana B. Beleslin-Cokic, Joyce M. Njoroge, Jeffery L. Miller, Mark T. Gladwin, Alan N. Schechter

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Figure 1

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Hydroxyurea and NO induce γ-globin gene expression in K562 cells. (a–c) ...
Hydroxyurea and NO induce γ-globin gene expression in K562 cells. (a–c) Hydroxyurea (white bars), CysNO (gray bars), and DETA-NONOate (black bars) induce γ-globin gene expression in K562 cells measured as femtomoles of γ-globin mRNA per 106 cells after 24 hours of treatment. Values represent means ± SEM (n = 3). *P < 0.05 and **P < 0.01 versus untreated cells (0).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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