title: Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase.
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 gamma-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 gamma-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.affiliation: Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Vladan P
authors.initials: VP
authors.lastname: Cokic
authors.forename: Reginald D
authors.initials: RD
authors.lastname: Smith
authors.forename: Bojana B
authors.initials: BB
authors.lastname: Beleslin-Cokic
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Njoroge
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Miller
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
mesh_terms: D006152:Cyclic GMP / Q000096:biosynthesis; D004789:Enzyme Activation; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006162:Guanylate Cyclase / Q000502:physiology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D020014:K562 Cells; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*
chemical_list: D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D005319:Fetal Hemoglobin; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D006918:Hydroxyurea