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Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells

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2008
199.pdf (737.2Kb)
Authors
Čokić, Vladan
Andrić, Silvana A.
Stojilković, Stanko S.
Noguchi, Constance T.
Schechter, Alan N.
Article (Published version)
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Abstract
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 mu M 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.

Source:
Blood, 2008, 111, 3, 1117-1123
Publisher:
  • Amer Soc Hematology, Washington
Funding / projects:
  • Ćelijski i molekularni mehanizmi regilacije hematopoeze (RS-145048)

DOI: 10.1182/blood-2007-05-088732

ISSN: 0006-4971

PubMed: 17993617

WoS: 000252792900031

Scopus: 2-s2.0-38949192565
[ Google Scholar ]
82
69
URI
http://rimi.imi.bg.ac.rs/handle/123456789/202
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
Institut za medicinska istraživanja
TY  - JOUR
AU  - Čokić, Vladan
AU  - Andrić, Silvana A.
AU  - Stojilković, Stanko S.
AU  - Noguchi, Constance T.
AU  - Schechter, Alan N.
PY  - 2008
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/202
AB  - 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 mu M 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.
PB  - Amer Soc Hematology, Washington
T2  - Blood
T1  - Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells
EP  - 1123
IS  - 3
SP  - 1117
VL  - 111
DO  - 10.1182/blood-2007-05-088732
UR  - conv_1897
ER  - 
@article{
author = "Čokić, Vladan and Andrić, Silvana A. and Stojilković, Stanko S. and Noguchi, Constance T. and Schechter, Alan N.",
year = "2008",
abstract = "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 mu M 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.",
publisher = "Amer Soc Hematology, Washington",
journal = "Blood",
title = "Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells",
pages = "1123-1117",
number = "3",
volume = "111",
doi = "10.1182/blood-2007-05-088732",
url = "conv_1897"
}
Čokić, V., Andrić, S. A., Stojilković, S. S., Noguchi, C. T.,& Schechter, A. N.. (2008). Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. in Blood
Amer Soc Hematology, Washington., 111(3), 1117-1123.
https://doi.org/10.1182/blood-2007-05-088732
conv_1897
Čokić V, Andrić SA, Stojilković SS, Noguchi CT, Schechter AN. Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. in Blood. 2008;111(3):1117-1123.
doi:10.1182/blood-2007-05-088732
conv_1897 .
Čokić, Vladan, Andrić, Silvana A., Stojilković, Stanko S., Noguchi, Constance T., Schechter, Alan N., "Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells" in Blood, 111, no. 3 (2008):1117-1123,
https://doi.org/10.1182/blood-2007-05-088732 .,
conv_1897 .

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