Hydroxyurea Generates Nitric Oxide in Human Erythroid Cells: Mechanisms for γ-Globin Gene Activation

Experimental Biology and Medicine - Tập 234 Số 11 - Trang 1374-1382 - 2009
Tzu‐Fang Lou1, Manisha Singh1, Ashley Mackie1, Wei Li1, Betty S. Pace1
1University of Texas at Dallas, Department of Molecular and Cell Biology, Richardson, Texas 75080

Tóm tắt

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 )ox-adiazolo(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.

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Experimental Biology and Medicine

Tập 234 Số 11

1374-1382

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