Hydroxyurea generates nitric oxide in human erythroid cells: Mechanisms for c-globin gene activation

Tzu Fang Lou, Manisha Singh, Ashley Mackie, Wei Li, Betty S. Pace

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Hydroxyurea (HU) induces fetal hemoglobin synthesis through activation of cyclic guanine monophosphate (cGMP) signaling. Studies in sickle cell patients demonstrated increased circulating nitric oxide (NO) levels after oral HU treatment. However, the direct measurement of NO in erythroid cells and its role in fetal hemoglobin induction have not been defined. Therefore, we quantified the level of nitrate and nitrite (NOx) generated by HU in human erythroid progenitors in the presence of three nitric oxide synthase inhibitors (NOS), including NG-monomethyl-L-arginine (L-NMMA). In addition, cGMP levels were measured in the presence or absence of the pathway inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, which blocks soluble guanylyl cyclase formation. HU treatment increased NOx levels and γ-globin transcription in K562 and primary erythroid cells, which was augmented when HU was combined with L-NMMA. Pretreatment with the cGMP pathway inhibitor reversed γ-gene activation by HU. These data demonstrate the direct stimulation of cellular NO and cGMP signaling in erythroid progenitors by HU as a possible mechanism for γ-globin gene activation.

Original languageEnglish (US)
Pages (from-to)1374-1382
Number of pages9
JournalExperimental Biology and Medicine
Issue number11
StatePublished - Nov 2009


  • Fetal hemoglobin
  • Hydroxyurea
  • Nitric oxide
  • Sickle-cell disease
  • cGMP

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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