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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1117-1123. Prepublished online as a Blood First Edition Paper on November 9, 2007; DOI 10.1182/blood-2007-05-088732. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-088732v1 111/3/1117    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 Cokic, V. P. Articles by Schechter, A. N. Search for Related Content PubMed PubMed Citation Articles by Cokic, V. P. Articles by Schechter, A. N. Related Collections Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells Vladan P. Cokic1, Silvana A. Andric2, Stanko S. Stojilkovic2, Constance T. Noguchi3, and Alan N. Schechter3 1 Laboratory of Experimental Hematology, Institute for Medical Research, Belgrade, Serbia; 2 Section on Cellular Signaling, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD; 3 Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD Hydroxyurea, a drug widely used for treating myeloproliferative diseases, has also been approved for the treatment of sickle cell disease by raising fetal hemoglobin (HbF). We have shown that nitric oxide (NO) and the soluble guanylyl cyclase (sGC) pathways are involved in hydroxyurea induction of HbF levels in erythroid progenitor cells (EPCs). We demonstrate now that during erythroid differentiation, endothelial NO synthase mRNA and protein levels decline steadily, as does the production of NO derivatives and cyclic adenosine monophosphate (cAMP) levels, but guanosine 3',5'-cyclic monophosphate (cGMP) levels are stable. Hydroxyurea increased intracellular cGMP levels and cAMP levels in EPCs. The NO donor, DEANONOate, induced much higher cGMP levels, but reduced cAMP levels. Hydroxyurea (1 mM) induced production of approximately 45 pM cGMP/minute/ng of purified sGC, similar to induction by 1 µM DEANONOate. We found that hydroxyurea and ProliNONOate produced iron-nitrosyl derivatives of sGC. Thus, we confirm that hydroxyurea can directly interact with the deoxy-heme of sGC, presumably by a free-radical nitroxide pathway, and activate cGMP production. These data add to an expanding appreciation of the role of hydroxyurea as an inducer of the NO/cGMP pathway in EPCs. These mechanisms may also be involved in the cytostatic effects of hydroxyurea, as well as the induction of HbF. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T.-F. Lou, M. Singh, A. Mackie, W. Li, and B. S. Pace Hydroxyurea Generates Nitric Oxide in Human Erythroid Cells: Mechanisms for {gamma}-Globin Gene Activation Experimental Biology and Medicine, November 1, 2009; 234(11): 1374 - 1382. [Abstract] [Full Text] [PDF] O. Sripichai, C. M. Kiefer, N. V. Bhanu, T. Tanno, S.-J. Noh, S.-H. Goh, J. E. Russell, C. L. Rognerud, C.-N. Ou, P. A. Oneal, et al. Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming Blood, September 10, 2009; 114(11): 2299 - 2306. [Abstract] [Full Text] [PDF]

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