Increased soluble guanylate cyclase activity in the red blood cells of sickle cell patients
Increased soluble guanylate cyclase activity in the red blood cells of sickle cell patients
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DOI：
10.1111/j.1365-2141.2004.04810.x
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发表时间：
2004-02-01
影响因子：
6.5
通讯作者：
Costa, FF
中科院分区：
文献类型：
--
作者：
Conran, N;Oresco-Santos, C;Costa, FF
据报道，可溶性鸟苷环化酶(SGC)的激活可上调红系细胞和原代红细胞中的γ-珠蛋白基因转录。SGC被一氧化氮(NO)激活，随后催化鸟苷三磷酸转化为环鸟苷一磷酸(CGMP)，从而介导各种生理反应。为探讨这一机制在镰状细胞患者红细胞中的重要性，测定了正常人、稳态镰状细胞患者(SS)和接受羟基脲(SS+HU)治疗的镰状细胞患者(SS+HU)的红细胞cGMP水平。SS患者RBC(SS RBC)中cGMP水平明显高于正常人RBC，SS+HU患者RBC中cGMP水平进一步升高。在SS/SS+HU患者中，cGMP水平与胎儿血红蛋白(HBF)水平相关，但与网织红细胞计数无关。此外，在细胞与NO供体孵育后，SS RBC的NO刺激的sGC活性显著高于正常RBC。这些结果首次证明了SGC介导的SS RBC中NO代谢的增加，而羟基脲则进一步促进了这种代谢。NO升高红细胞内cGMP水平可能是诱导HBF等红细胞功能的机制之一，是治疗镰状细胞病的可能靶点。
Activation of soluble guanylate cyclase (sGC) has been reported to up-regulate gamma-globin gene transcription in erythroid cell lines and primary erythroblasts. sGC is activated by nitric oxide (NO), subsequently catalysing the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which mediates various physiological responses. To study the importance of this mechanism in the erythroid cells of sickle cell patients, cGMP levels were measured in the red blood cells (RBC) of normal individuals, steady-state sickle cell patients (SS) and SS patients on hydroxyurea (HU) therapy (SS + HU). cGMP levels were found to be significantly higher in RBC of SS patients (SS RBC) than in RBC of normal individuals, and were further increased in RBC of SS + HU patients. cGMP levels correlated with fetal haemoglobin (HbF) levels in SS/SS + HU patients, but not with reticulocyte count. Furthermore, NO-stimulated sGC activity, following incubation of cells with a NO donor, was significantly greater in SS RBC than in normal RBC. These results demonstrate, for the first time, an increased metabolism of NO mediated by sGC in the SS RBC, which is further increased by hydroxyurea. Augmentation of cGMP levels by NO in erythroid cells may constitute a mechanism for induction of HbF and other erythrocyte functions and represent a possible therapeutic target for treatment of sickle cell disease.