Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis.
Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis.
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DOI：
10.1371/journal.pone.0144561
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gaensler KM
中科院分区：
文献类型：
--
作者：
Ikuta T;Sellak H;Odo N;Adekile AD;Gaensler KM
一氧化氮（NO）-cGMP信号转导的生理效应已引起人们的极大关注，但实际上对其血液学效应一无所知。我们首次报道了cGMP信号诱导人γ-珠蛋白基因表达。为了开发贫血的新疗法，我们在这里研究了NO-cGMP信号转导在体内和体外的血液学作用。我们用NO处理野生型小鼠以激活可溶性鸟苷酸环化酶（sGC），这是cGMP信号传导的关键酶。与未处理的小鼠相比，NO处理的小鼠具有更高的红细胞计数和总血红蛋白，但减少了白细胞计数，这表明当被激活时，NO-cGMP信号传导对体内多种类型的血细胞发挥造血作用。我们接下来产生了在红系和髓系细胞中过表达大鼠sGC的小鼠。sGC的强制表达激活了两种谱系细胞中的cGMP信号传导。与非转基因同窝小鼠相比，sGC小鼠表现出与NO处理小鼠相似的血液学变化。一致的，膜渗透性cGMP促进造血祖细胞向红系细胞的分化，但通过控制多个谱系特异性转录因子抑制它们向髓系细胞的分化。在携带人β-珠蛋白基因座的sGC小鼠中，人γ-珠蛋白基因表达以低但可感知的水平诱导。总之，这些结果表明，NO-cGMP信号能够刺激红细胞生成在体外和体内设置通过控制多种谱系特异性转录因子的表达，表明cGMP信号上调红细胞生成在基因转录水平。NO-cGMP信号轴可能构成体内刺激红细胞生成的新靶点。
Much attention has been directed to the physiological effects of nitric oxide (NO)-cGMP signaling, but virtually nothing is known about its hematologic effects. We reported for the first time that cGMP signaling induces human γ-globin gene expression. Aiming at developing novel therapeutics for anemia, we examined here the hematologic effects of NO-cGMP signaling in vivo and in vitro. We treated wild-type mice with NO to activate soluble guanylate cyclase (sGC), a key enzyme of cGMP signaling. Compared to untreated mice, NO-treated mice had higher red blood cell counts and total hemoglobin but reduced leukocyte counts, demonstrating that when activated, NO-cGMP signaling exerts hematopoietic effects on multiple types of blood cells in vivo. We next generated mice which overexpressed rat sGC in erythroid and myeloid cells. The forced expression of sGCs activated cGMP signaling in both lineage cells. Compared with non-transgenic littermates, sGC mice exhibited hematologic changes similar to those of NO-treated mice. Consistently, a membrane-permeable cGMP enhanced the differentiation of hematopoietic progenitors toward erythroid-lineage cells but inhibited them toward myeloid-lineage cells by controlling multiple lineage-specific transcription factors. Human γ-globin gene expression was induced at low but appreciable levels in sGC mice carrying the human β-globin locus. Together, these results demonstrate that NO-cGMP signaling is capable of stimulating erythropoiesis in both in vitro and vivo settings by controlling the expression of multiple lineage-specific transcription factors, suggesting that cGMP signaling upregulates erythropoiesis at the level of gene transcription. The NO-cGMP signaling axis may constitute a novel target to stimulate erythropoiesis in vivo.