Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia
Manik C. Ghosh, De-Liang Zhang, Hayden Ollivierre, Michael A. Eckhaus, Tracey A. Rouault
Manik C. Ghosh, De-Liang Zhang, Hayden Ollivierre, Michael A. Eckhaus, Tracey A. Rouault
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Research Article Hematology

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

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.

Authors

Manik C. Ghosh, De-Liang Zhang, Hayden Ollivierre, Michael A. Eckhaus, Tracey A. Rouault

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Figure 5

The reduced life expectancy of VhlR200W mice was alleviated by Tempol supplementation when Irp1 was present.

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The reduced life expectancy of VhlR200W mice was alleviated by Tempol su...
The survival curves of WT, VhlR200W, and VhlR200W Irp1–/– mice on a control or Tempol-supplemented diet showed that VhlR200W mice on a control diet died at significantly higher survival rates than did WT mice on a control diet, whereas no significant difference was observed in the survival rates between Tempol-supplemented VhlR200W and WT mice (on either a control or Tempol-supplemented diet). Moreover, the beneficial effect of Tempol was lost when Irp1 was absent in these VhlR200W mice. n = 180 WT mice on a control diet; n = 34 WT mice on a Tempol diet; n = 76 VhlR200W mice on a control diet; n = 43 VhlR200W mice on a Tempol diet; n = 35 VhlR200W Irp1–/– mice on a control diet; and n = 18 VhlR200W Irp1–/– mice on a Tempol diet . Statistical analyses of mouse survival curves were performed with a log-rank Mantel-Cox test using GraphPad Prism software.