title: Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α.
abstract: 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.
authors: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
authors: Manik C
authors: MC
authors: Ghosh
authors: De-Liang
authors: DL
authors: Zhang
authors: Suh Young
authors: SY
authors: Jeong
authors: Gennadiy
authors: G
authors: Kovtunovych
authors: Hayden
authors: H
authors: Ollivierre-Wilson
authors: Audrey
authors: A
authors: Noguchi
authors: Tiffany
authors: T
authors: Tu
authors: Thomas
authors: T
authors: Senecal
authors: Gabrielle
authors: G
authors: Robinson
authors: Daniel R
authors: DR
authors: Crooks
authors: Wing-Hang
authors: WH
authors: Tong
authors: Kavitha
authors: K
authors: Ramaswamy
authors: Anamika
authors: A
authors: Singh
authors: Brian B
authors: BB
authors: Graham
authors: Rubin M
authors: RM
authors: Tuder
authors: Zu-Xi
authors: ZX
authors: Yu
authors: Michael
authors: M
authors: Eckhaus
authors: Jaekwon
authors: J
authors: Lee
authors: Danielle A
authors: DA
authors: Springer
authors: Tracey A
authors: TA
authors: Rouault
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D004032:Diet; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood; D006471:Gastrointestinal Hemorrhage / Q000097:blood / Q000150:complications / Q000473:pathology; D017353:Gene Deletion; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications* / Q000473:pathology; D007501:Iron / Q000494:pharmacology; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D008136:Longevity; D051379:Mice; D008954:Models, Biological; D009410:Nerve Degeneration / Q000097:blood / Q000150:complications / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D011086:Polycythemia / Q000097:blood / Q000150:complications* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019332:Endothelin-1; D004921:Erythropoietin; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D000099162:Endothelial PAS Domain-Containing Protein 1
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