Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease.
Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease.
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DOI：
10.1111/bjh.16671
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发表时间：
2020-08
影响因子：
6.5
通讯作者：
Low PS
中科院分区：
文献类型：
--
作者：
Noomuna P;Risinger M;Zhou S;Seu K;Man Y;An R;Sheik DA;Wan J;Little JA;Gurkan UA;Turrini FM;Kalfa T;Low PS
对于镰状血红蛋白（HbS）中谷氨酸向缬氨酸的取代如何导致镰状细胞病（SCD），人们提出了许多假设。我们提出并记录了一种新的机制，其中条带3酪氨酸磷酸化升高引发引起血管闭塞和SCD症状的后遗症。在这个机制中，HbS的变性和血红素的释放产生细胞内氧化剂，引起红细胞酪氨酸磷酸酶的抑制，从而允许Band 3的组成型酪氨酸磷酸化。这种磷酸化反过来诱导谱蛋白-肌动蛋白细胞骨架从膜上解离，导致膜弱化，释放膜源性微粒（启动凝血级联）和释放无细胞HbS（消耗一氧化氮）并激活内皮细胞以表达粘附受体)。这些过程促进导致SCD的血管闭塞事件。我们进一步表明，Syk酪氨酸激酶抑制剂阻断带3酪氨酸磷酸化，阻止无细胞Hb的释放，抑制膜源性微粒的排出，增加镰状细胞的变形能力，减少镰状细胞与人内皮细胞的粘附，并增强镰状细胞通过微血管的流动。鉴于伊马替尼（一种Syk抑制剂）成功治疗镰状细胞病症状的报道，我们建议Syk酪氨酸激酶抑制剂值得重新利用作为SCD的潜在治疗方法。
Many hypotheses have been proposed to explain how a glutamate to valine substitution in sickle haemoglobin (HbS) can cause sickle cell disease (SCD). We propose and document a new mechanism in which elevated tyrosine phosphorylation of Band 3 initiates sequelae that cause vaso-occlusion and the symptoms of SCD. In this mechanism, denaturation of HbS and release of heme generate intracellular oxidants which cause inhibition of erythrocyte tyrosine phosphatases, thus permitting constitutive tyrosine phosphorylation of Band 3. This phosphorylation in turn induces dissociation of the spectrin-actin cytoskeleton from the membrane, leading to membrane weakening, discharge of membrane-derived microparticles (which initiate the coagulation cascade) and release of cell-free HbS (which consumes nitric oxide) and activates the endothelium to express adhesion receptors). These processes promote vaso-occlusive events which cause SCD. We further show that inhibitors of Syk tyrosine kinase block Band 3 tyrosine phosphorylation, prevent release of cell-free Hb, inhibit discharge of membrane-derived microparticles, increase sickle cell deformability, reduce sickle cell adhesion to human endothelial cells, and enhance sickle cell flow through microcapillaries. In view of reports that imatinib (a Syk inhibitor) successfully treats symptoms of sickle cell disease, we suggest that Syk tyrosine kinase inhibitors warrant repurposing as potential treatments for SCD.
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影响因子：
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