Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia

J Clin Invest. 2018 Apr 2;128(4):1317-1325. doi: 10.1172/JCI97684. Epub 2018 Feb 26.

Abstract

Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2α, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1-knockout (Irp1-knockout) mice developed erythrocytosis/polycythemia through translational derepression of Hif2α, suggesting that IRP1 could be a therapeutic target to treat Chuvash polycythemia. Here, we fed VhlR200W mice supplemented with Tempol, a small, stable nitroxide molecule and observed that Tempol decreased erythropoietin production, corrected splenomegaly, normalized hematocrit levels, and increased the lifespans of these mice. We attribute the reversal of erythrocytosis/polycythemia to translational repression of Hif2α expression by Tempol-mediated increases in the IRE-binding activity of Irp1, as reversal of polycythemia was abrogated in VhlR200W mice in which Irp1 was genetically ablated. Thus, a new approach to the treatment of patients with Chuvash polycythemia may include dietary supplementation of Tempol, which decreased Hif2α expression and markedly reduced life-threatening erythrocytosis/polycythemia in the VhlR200W mice.

Keywords: Drug therapy; Hematology; Pharmacology; Translation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cyclic N-Oxides / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Iron Regulatory Protein 1 / genetics
  • Iron Regulatory Protein 1 / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Polycythemia / drug therapy*
  • Polycythemia / genetics
  • Polycythemia / metabolism
  • Polycythemia / pathology
  • Protein Biosynthesis / drug effects*
  • Spin Labels

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cyclic N-Oxides
  • Spin Labels
  • endothelial PAS domain-containing protein 1
  • Iron Regulatory Protein 1
  • tempol