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

Manik C. Ghosh, De Liang Zhang, Suh Young Jeong, Gennadiy Kovtunovych, Hayden Ollivierre-Wilson, Audrey Noguchi, Tiffany Tu, Thomas Senecal, Gabrielle Robinson, Daniel R. Crooks, Wing Hang Tong, Kavitha Ramaswamy, Anamika Singh, Brian B. Graham, Rubin M. Tuder, Zu Xi Yu, Michael Eckhaus, Jaekwon Lee, Danielle A. Springer, Tracey A. Rouault

Research output: Contribution to journalArticle

103 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)271-281
Number of pages11
JournalCell Metabolism
Volume17
Issue number2
DOIs
StatePublished - Feb 5 2013

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Ghosh, M. C., Zhang, D. L., Jeong, S. Y., Kovtunovych, G., Ollivierre-Wilson, H., Noguchi, A., Tu, T., Senecal, T., Robinson, G., Crooks, D. R., Tong, W. H., Ramaswamy, K., Singh, A., Graham, B. B., Tuder, R. M., Yu, Z. X., Eckhaus, M., Lee, J., Springer, D. A., & Rouault, T. A. (2013). Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. Cell Metabolism, 17(2), 271-281. https://doi.org/10.1016/j.cmet.2012.12.016