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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.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

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

From the Institute of Medical Research, and the Institute of Endocrinology, Diabetes and Diseases of Metabolism, Belgrade, Serbia and Montenegro; the Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, and the Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD.

Hydroxyurea is a cell-cycle-specific drug that 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 (HUVECs) 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 Ser1177 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 HUVECs. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance the effect of NO in myeloproliferative diseases. (Blood. 2006;108:184-191)


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