Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α.
Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α.
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DOI：
10.1016/j.cmet.2012.12.016
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发表时间：
2013-02-05
期刊：
影响因子：
29
通讯作者：
Rouault TA
中科院分区：
文献类型：
--
作者：
Ghosh MC;Zhang DL;Jeong SY;Kovtunovych G;Ollivierre-Wilson H;Noguchi A;Tu T;Senecal T;Robinson G;Crooks DR;Tong WH;Ramaswamy K;Singh A;Graham BB;Tuder RM;Yu ZX;Eckhaus M;Lee J;Springer DA;Rouault TA
铁调节蛋白1和2(Irps)转录后调控含有铁反应元件(IRE)序列的转录本的表达，包括铁蛋白、铁蛋白、转铁蛋白受体和缺氧诱导因子2α(HIF2α)。我们在这里报道，IRP1靶向缺失的小鼠出现了肺动脉高压和红细胞增多症，而低铁饮食加剧了这种情况。缺铁小鼠的红细胞压积增加到65%，许多红细胞增多症小鼠死于腹部出血。IRP1缺失使IRP1α小鼠肾脏HIF2−/−蛋白表达增强，导致促红细胞生成素(EPO)表达增加、红细胞增多症和伴随组织铁缺乏。肺内皮细胞HIF2α表达增加可诱导ET-1高表达，可能是导致IRP1−/−小鼠肺动脉高压的原因之一。我们的结果揭示了贫血是铁缺乏的早期生理后果，突出了Irp1在调节红细胞生成和铁分布方面的生理学意义，并为研究肺动脉高压的分子发病机制提供了重要的见解。
Iron regulatory proteins 1 and 2 (Irps) post-transcriptionally 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.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
6
作者：
Graham, Brian B.;Mentink-Kane, Margaret M.;Tuder, Rubin M.
通讯作者：
Tuder, Rubin M.
影响因子：
15.9
作者：
Hickey, Michele M.;Lam, Jennifer C.;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
影响因子：
56.9
作者：
Meyron-Holtz, EG;Ghosh, MC;Rouault, TA
通讯作者：
Rouault, TA
影响因子：
20.3
作者：
Galy, B;Ferring, D;Hentze, MW
通讯作者：
Hentze, MW