Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase
Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase
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DOI：
10.1172/jci200316672
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发表时间：
2003-01-01
影响因子：
15.9
通讯作者：
Schechter, AN
中科院分区：
文献类型：
--
作者：
Cokic, VP;Smith, RD;Schechter, AN
羟基脲治疗镰状细胞病患者可增加胎儿血红蛋白（HbF），从而减少血红蛋白S聚合和临床并发症。尽管其用于治疗骨髓增生性疾病超过30年，但其作用机制仍不确定。最近的研究表明，羟基脲产生一氧化氮（NO）自由基在体内，因此，我们假设，NO供体的属性可能会决定血红蛋白的表型。我们用一氧化氮供体S-亚硝基半胱氨酸（CysNO）处理K562红白血病细胞和人红系祖细胞，发现γ-珠蛋白mRNA和HbF蛋白的诱导与我们用羟基脲观察到的相似，具有剂量和时间依赖性。羟基脲和CysNO均增加cGMP水平，鸟苷酸环化酶抑制剂ODQ、NS 2028和LY 83，538均消除了羟基脲和CysNO诱导的γ-珠蛋白表达。这些数据提供了强有力的证据，一个NO衍生的机制，通过羟基脲的HbF诱导，并建议基于NO释放或增强剂的治疗的可能性。
Hydroxyurea treatment of patients with sickle-cell disease increases fetal hemoglobin (HbF), which reduces hemoglobin S polymerization and clinical complications. Despite its use in the treatment of myeloproliferative diseases for over 30 years, its mechanism of action remains uncertain. Recent studies have demonstrated that hydroxyurea generates the nitric oxide (NO) radical in vivo, and we therefore hypothesized that NO-donor properties might determine the hemoglobin phenotype. We treated both K562 erythroleukemic cells and human erythroid progenitor cells with S-nitrosocysteine (CysNO), an NO donor, and found similar dose- and time-dependent induction of gamma-globin mRNA and HbF protein as we observed with hydroxyurea. Both hydroxyurea and CysNO increased cGMP levels, and the guanylyl cyclase inhibitors ODQ, NS 2028, and LY 83,538 abolished both the hydroxyurea- and CysNO-induced gamma-globin expression. These data provide strong evidence for an NO-derived mechanism for HbF induction by hydroxyurea and suggest possibilities for therapies based on NO-releasing or -potentiating agents.