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Blood, 1 July 2006, Vol. 108, No. 1, pp. 184-191. Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-11-4454. This Article Full Text (PDF) All Versions of this Article: 2005-11-4454v1 108/1/184    most recent Alert me when this article is cited Alert me if a correction is posted 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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 10, 2005 Accepted February 23, 2006 Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells Vladan P Cokic, Bojana B Beleslin-Cokic, Melanija Tomic, Stanko S Stojilkovic, Constance T Noguchi, and Alan N Schechter* Institute of Medical Research, Belgrade, Serbia/Montenegro Institute of Endocrinology, Diabetes and Diseases of Metabolism, Belgrade, Serbia/Montenegro Endocrinology and Reproduction Research Branch, National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland, USA * Corresponding author; email: aschecht{at}helix.nih.gov. Hydroxyurea is a cell cycle-specific drug, which has been used to treat myeloproliferative diseases and sickle cell anemia. We have recently shown that hydroxyurea, like nitric oxide (NO)-donor compounds, increased cGMP levels in human erythroid cells. We show now that hydroxyurea increases endothelial cell production of NO; this induction of NO in human umbilical vein endothelial cells (HUVEC) and human bone marrow endothelial cell line (TrHBMEC) is blocked by competitive inhibitors of NO synthase (NOS), such as NG-nitro-L-arginine-methyl ester (L-NAME) and NG-nitro-L-arginine. It is dependent on cAMP-dependent protein kinase (PKA) and protein kinase B (PKB/Akt) activity. We found that hydroxyurea dose- and time-dependently induced rapid and transient phosphorylation of eNOS at Ser-1177 in a PKA-dependent manner; inhibitors of PKB/Akt could partially abrogate this effect. In addition, hydroxyurea induced cAMP and cGMP levels in a dose-dependent manner, as well as levels of intracellular calcium in HUVEC. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance its effects in myeloproliferative diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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