Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α

GhoshM.C.; ZhangD.-L.; JeongS.Y.; KovtunovychG.; Ollivierre-WilsonH.; NoguchiA.; TuT.; SenecalT.; RobinsonG.; CrooksD.R.; TongW.-H.; RamaswamyK.; SinghA.; GrahamB.B.; TuderR.M.; YuZ.-X.; EckhausM.; LeeJ.; SpringerD.A.; RouaultT.A.

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Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α

机译：铁调节蛋白1的缺失通过HIF2α的翻译抑制导致小鼠红细胞增多症和肺动脉高压

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Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1-/- mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1-/- mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.

机译：铁调节蛋白（Irps）1和2在转录后控制包含铁反应性元素（IRE）序列的转录物的表达，这些序列包括铁蛋白，铁转运蛋白，转铁蛋白受体和缺氧诱导因子2α（HIF2α）。我们在此报告，靶向缺失Irp1的小鼠发生了肺动脉高压和红细胞增多症，低铁饮食会加剧这种情况。铁饥饿的小鼠中的血细胞比容升高至65％，许多多细胞性小鼠死于腹腔出血。 Irp1缺失增强了Irp1-/-小鼠肾脏中HIF2α蛋白的表达，导致促红细胞生成素（EPO）表达，红细胞增多症和组织铁缺乏症。肺内皮细胞中HIF2α表达的增加诱导了内皮素1的高表达，这可能导致了Irp1-/-小鼠的肺动脉高压。我们的研究结果揭示了贫血是缺铁的早期生理后果的原因，突出了Irp1在调节红细胞生成和铁分布中的生理意义，并为肺动脉高压的分子发病机理提供了重要的见识。

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《Cell metabolism》 |2013年第2期|共11页
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GhoshM.C.; ZhangD.-L.; JeongS.Y.; KovtunovychG.; Ollivierre-WilsonH.; NoguchiA.; TuT.; SenecalT.; RobinsonG.; CrooksD.R.; TongW.-H.; RamaswamyK.; SinghA.; GrahamB.B.; TuderR.M.; YuZ.-X.; EckhausM.; LeeJ.; SpringerD.A.; RouaultT.A.;
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1. Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α [J] . GhoshM.C., ZhangD.-L., JeongS.Y., Cell metabolism . 2013,第2期

机译：铁调节蛋白1的缺失通过HIF2α的翻译抑制导致小鼠红细胞增多症和肺动脉高压
2. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. [J] . LaVaute T, Smith S, Cooperman S, Nature Genetics . 2001,第2期

机译：有针对性地删除编码铁调节蛋白2的基因会导致小鼠铁代谢和神经退行性疾病的调节异常。
3. Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis [J] . TawfikA., Gnana-PrakasamJ.P., SmithS.B., Investigative ophthalmology & visual science . 2014,第6期

机译：老鼠体内的铁调节蛋白hemojuvelin缺失会导致视网膜血管生成和血管生成异常，以及反应性神经胶质增生
4. Fully Automatic Cardiac Segmentation And Quantification For Pulmonary Hypertension Analysis Using Mice Cine Mr Images [C] . Blanca Zufiria, Maialen Stephens, Maria Jesús Sánchez, IEEE International Symposium on Biomedical Imaging . 2021

机译：使用小鼠凝聚MR图像全自动心脏分割和肺动脉高压分析量化
5. The effects of pulmonary hypertension on the mechanical properties of arteries in Cav-1-/- mice [D] . Moreno, Justin 2012

机译：肺动脉高压对Cav-1-/-小鼠动脉机械特性的影响
6. Deletion of Iron Regulatory Protein 1 Causes Polycythemia and Pulmonary Hypertension in Mice through Translational De-repression of HIF2α [O] . Manik C. Ghosh, De-Liang Zhang, Suh Young Jeong, -1

机译：铁调节蛋白1的缺失通过HIF2α的翻译去阻遏导致红细胞增多症和肺动脉高压小鼠
7. Deletion of Iron Regulatory Protein 1 Causes Polycythemia and Pulmonary Hypertension in Mice through Translational Derepression of HIF2α [O] . Ghosh Manik C., Zhang De-Liang, Jeong Suh Young, 2013

机译：铁调节蛋白1的缺失通过HIF2α的翻译抑制导致小鼠红细胞增多症和肺动脉高压。

Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α

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