High expression of the cGMP-specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils
High expression of the cGMP-specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils
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DOI：
10.1111/j.1365-2141.2008.07264.x
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发表时间：
2008-09-01
影响因子：
6.5
通讯作者：
Conran, Nicola
中科院分区：
文献类型：
--
作者：
Almeida, Camila Bononi;Traina, Fabiola;Conran, Nicola
细胞内环磷酸鸟苷 (cGMP) 的调节可能是镰状细胞病 (SCD) 治疗靶点的特征； cGMP 依赖性信号传导对于胎儿红细胞血红蛋白的诱导可能很重要，并在白细胞中发挥抗炎功能。由于调节细胞内 cGMP 的磷酸二酯酶 (PDE) 的抑制可导致组织特异性 cGMP 升高，因此我们研究了健康对照、稳态 SCD 患者和接受羟基脲治疗 (SCDHC) 的 SCD 患者的网织红细胞和中性粒细胞中 cGMP 特异性 PDE（-1A、-5A 和 -9A）的基因表达。 PDE9A 基因在多种细胞类型中表达；然而，在中性粒细胞、网织红细胞、CD34(+)衍生的红系细胞和K562红白血病细胞中发现高表达，表明造血细胞高表达。然而，与对照细胞相比，SCD 个体的网织红细胞和中性粒细胞中的 PDE9A 基因表达显着较高； Western blotting证实SCD中性粒细胞和K562细胞中产生PDE9A蛋白。用特异性抑制剂 BAY73-6691 抑制 PDE9A 酶，可显着增加 K562 细胞中 γ 球蛋白基因 (HBG) 的产生，并逆转 SCD 中性粒细胞粘附特性的增加。由于造血细胞内 cGMP 的升高可能对 SCD 有益，因此 PDE9A 相对有限的组织分布表明它可能代表一个值得进一步研究的新药物靶点。
Modulation of intracellular cyclic guanosine monophosphate (cGMP) may characterize a therapeutic target for sickle cell disease (SCD); cGMP-dependent signalling may be important for erythroid foetal haemoglobin induction and exert anti-inflammatory functions in leucocytes. As the inhibition of phosphodiesterases (PDEs), which regulate intracellular cGMP, can result in tissue-specific elevation of cGMP, we studied the gene expressions of cGMP-specific PDEs (-1A, -5A and -9A) in the reticulocytes and neutrophils of healthy controls, steady-state SCD patients and SCD patients on hydroxycarbamide therapy (SCDHC). PDE9A gene expression was found in numerous cell types; however, high expression was found in neutrophils, reticulocytes, CD34(+)-derived erythroid cells and K562 erythroleukaemic cells, indicating a high haematopoietic cell expression. PDE9A gene expression was, however, significantly higher in the reticulocytes and neutrophils of SCD individuals, compared to control cells; Western blotting confirmed the production of PDE9A protein in SCD neutrophils and K562 cells. Inhibition of PDE9A enzyme with the specific inhibitor, BAY73-6691, significantly increased production of the gamma-globin gene (HBG) in K562 cells and reversed the increased adhesive properties of SCD neutrophils. Since elevation of haematopoietic intracellular cGMP may be beneficial in SCD, the relatively limited tissue distribution of PDE9A suggests that it could represent a novel drug target worthy of further study.