TY - JOUR
T1 - Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α
AU - Ghosh, Manik C.
AU - Zhang, De Liang
AU - Jeong, Suh Young
AU - Kovtunovych, Gennadiy
AU - Ollivierre-Wilson, Hayden
AU - Noguchi, Audrey
AU - Tu, Tiffany
AU - Senecal, Thomas
AU - Robinson, Gabrielle
AU - Crooks, Daniel R.
AU - Tong, Wing Hang
AU - Ramaswamy, Kavitha
AU - Singh, Anamika
AU - Graham, Brian B.
AU - Tuder, Rubin M.
AU - Yu, Zu Xi
AU - Eckhaus, Michael
AU - Lee, Jaekwon
AU - Springer, Danielle A.
AU - Rouault, Tracey A.
N1 - Funding Information:
This work was supported by the intramural programs of NICHD and NHLBI. We thank Gregory Holmes-Hampton for helpful discussions, Michele Allen for her help in mouse studies, Shawn Kozlov for blood gas measurements, and Javier Seravalli for performing metal measurements. R.M.T.’s research was supported by NIH (RC1HL100849). M.C.G. and D.-L.Z. designed the study, generated data, performed analyses, and wrote the paper. S.Y.J. and D.A.S. generated data, performed analyses, and wrote the paper. G.K., A.N., D.R.C., B.B.G., Z.-X.Y., M.E., and J.L. generated data and performed analyses. H.O.-W., T.T., T.S., G.R., K.R., and A.S. generated data. W.-H.T. and R.M.T. provided substantial intellectual contribution. T.A.R. designed the study, performed analyses, and wrote the paper.
PY - 2013/2/5
Y1 - 2013/2/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2012.12.016
DO - 10.1016/j.cmet.2012.12.016
M3 - Article
C2 - 23395173
AN - SCOPUS:84873338684
SN - 1550-4131
VL - 17
SP - 271
EP - 281
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -