HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis
HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis
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DOI：
10.1007/s00109-015-1294-y
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发表时间：
2015-08-01
影响因子：
4.7
通讯作者：
Prchal, Josef T.
中科院分区：
文献类型：
--
作者：
Song, Jihyun;Yoon, Donghoon;Prchal, Josef T.
在长时间缺氧期间，缺氧诱导因子（HIF）介导红细胞生成增加，导致红细胞（RBC）质量增加和红细胞增多症。一旦恢复到常氧状态，增加的RBC质量突然被缺氧形成的年轻RBC的优先破坏过度校正，这种现象称为新细胞溶解。涉及新细胞溶解的分子和生化机制尚不清楚。我们通过将小鼠暴露于12%的氧气10天，然后恢复到常氧状态，建立了新细胞溶解的小鼠模型。恢复常氧后，RBC中活性氧（ROS）过度积累，这是由于网织红细胞线粒体质量增加，与Bnip 3L转录物（Bnip 3L介导网织红细胞线粒体自噬）减少和过氧化氢酶活性降低相关。在缺氧期间，上调的miR-21导致年轻RBC中过氧化氢酶活性降低。此外，抗氧化剂和血浆过氧化氢酶减弱了新细胞溶解，并在组成性高表达HIF的小鼠中钝化。在研究的人类新生儿中，我们报告的数据支持在生命的第一周内存在新细胞溶解。总之，这些实验表明，导致新细胞溶解的主要机制涉及（1）在缺氧期间产生具有低过氧化氢酶的年轻RBC和（2）在恢复到常氧后年轻RBC的溶解，由来自增加的线粒体质量的ROS介导。
During prolonged hypoxia, hypoxia-inducible factors (HIFs) mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass and polycythemia. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. The molecular and biochemical mechanisms involved in neocytolysis are unknown. We developed a murine model of neocytolysis by exposing mice to 12 % oxygen for 10 days followed by return to normoxia. Upon return to normoxia, there was excessive accumulation of reactive oxygen species (ROS) in RBCs from an increased reticulocyte mitochondrial mass correlating with decreased Bnip3L transcripts (Bnip3L mediates reticulocyte mitophagy) and reduced catalase activity. During hypoxia, upregulated miR-21 resulted in low catalase activity in young RBCs. Furthermore, neocytolysis was attenuated by antioxidants and plasma catalase and blunted in mice that had constitutively high expression of HIFs. Among human neonates studied, we report data supporting the existence of neocytolysis during the first week of life. Together, these experiments indicate that the major mechanisms causing neocytolysis involve (1) production of young RBCs with low catalase during hypoxia and (2) lysis of the young RBCs after return to normoxia, mediated by ROS from an increased mitochondrial mass.