Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease
Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease
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DOI：
10.1016/j.exphem.2017.02.003
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发表时间：
2017-06-01
影响因子：
2.6
通讯作者：
Rivers, Angela
中科院分区：
文献类型：
--
作者：
Jagadeeswaran, Ramasamy;Vazquez, Benjamin A.;Rivers, Angela
镰状细胞病（SCD）是一种遗传性血液病，由一种点突变引起，使血红蛋白在缺氧时易于聚合，影响着全世界数百万人。SCD的表现包括慢性溶血性贫血、炎症、疼痛性血管闭塞危象、多系统器官损伤和预期寿命缩短。SCD病理生理学的一部分是SCD红细胞（RBC）中细胞内活性氧（ROS）的过度形成，这加速了它们的溶血。正常RBC前体在终末分化过程中消除其线粒体。引人注目的是，我们观察到与健康个体相比，SCD患者血液样本中保留线粒体的RBC百分比增加。此外，使用实验性SCD小鼠模型，我们证明了SCD中ROS水平过高与这种异常的线粒体滞留有关。有趣的是，在SCD小鼠模型中，LSD 1抑制剂RN-1和线粒体自噬诱导剂哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂西罗莫司增加了RBC寿命并减少了ROS积累，同时减少了保留RBC的RBC。此外，用RN-1处理的SCD小鼠的基因表达分析显示线粒体自噬基因的表达增加。我们的研究结果表明，减少线粒体保留红细胞可能提供一种新的治疗方法，以防止过多的活性氧在SCD。版权所有（C）2017 ISEH -国际实验血液学学会。爱思唯尔公司出版
Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs), which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs retaining mitochondria in SCD patient blood samples compared with healthy individuals. In addition, using an experimental SCD mouse model, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention. Interestingly, the LSD1 inhibitor, RN-1, and the mitophagy-inducing agent mammalian target of rapamycin (mTOR) inhibitor, sirolimus, increased RBC lifespan and reduced ROS accumulation in parallel with reducing mitochondria-retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria -retaining RBCs may provide a new therapeutic approach to preventing excessive ROS in SCD. Copyright (C) 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.