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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3945-3950. Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-08-2969. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2969v1 103/10/3945    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Haynes, J. Articles by Pace, B. Search for Related Content PubMed PubMed Citation Articles by Haynes, J., Jr Articles by Pace, B. Related Collections Signal Transduction Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the L-arginine–nitric oxide signaling pathway Johnson Haynes, Jr, B. Surendra Baliga, Boniface Obiako, Solomon Ofori-Acquah, and Betty Pace From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX. Induction of fetal hemoglobin (Hb F) is an important therapeutic tool in ameliorating complications of sickle cell disease. Nitric oxide has been implicated in the mechanism of Hb F synthesis induced by hydroxyurea (HU). This study examined whether zileuton (ZL), a structural analog of hydroxyurea, possessed Hb F–inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in -globin expression in K562 cells. This effect was confirmed by a dose-dependent increase in Hb F synthesis in erythroid progenitors from individuals with sickle cell anemia and normal hemoglobin genotypes. L-arginine had no effect on Hb F production; however, it dose-dependently inhibited ZL's ability to induce Hb F. The nitric oxide synthase inhibitor NG-monomethyl–L-arginine (L-NMMA) inhibited L-arginine's effect and restored ZL-mediated increase in Hb F synthesis. In addition, 8-PCPT–cGMP (8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate) inhibited ZL-mediated induction of Hb F synthesis. When comparing L-NMMA effects alone on ZL and HU, a partial reversal of increased Hb F synthesis was seen only with HU. Neither L-arginine alone nor L-arginine in combination with L-NMMA effected hydroxyurea-mediated induction of Hb F synthesis. This study demonstrates that ZL induces Hb F through a mechanism that involves L-arginine/nitric oxide/cGMP in a manner distinctly different from HU. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. P. Cokic, S. A. Andric, S. S. Stojilkovic, C. T. Noguchi, and A. N. Schechter Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells Blood, February 1, 2008; 111(3): 1117 - 1123. [Abstract] [Full Text] [PDF] A. Bank Regulation of human fetal hemoglobin: new players, new complexities Blood, January 15, 2006; 107(2): 435 - 443. [Abstract] [Full Text] [PDF]

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