Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia
Manik C. Ghosh, … , Michael A. Eckhaus, Tracey A. Rouault
Manik C. Ghosh, … , Michael A. Eckhaus, Tracey A. Rouault
Published April 2, 2018; First published February 26, 2018
Citation Information: J Clin Invest. 2018;128(4):1317-1325. https://doi.org/10.1172/JCI97684.
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Categories: 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 4

Genetic ablation of Irp1 significantly increased polycythemia inVhlR200W mice, which became refractory to Tempol, confirming that Tempol activates Irp1 to ameliorate the polycythemia in VhlR200W mice, and Tempol also partially protects WT mice from hypoxic polycythemia/erythrocytosis.

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Genetic ablation of Irp1 significantly increased polycythemia inVhlR200W...
(A) Hematocrit (determined by capillary tube centrifugation), (B) hemoglobin, and (C) RBC levels of 5- to 8-month-old WT, Irp1–/–, and VhlR200W Irp1–/– mice fed a control or Tempol-supplemented diet revealed that Tempol did not decrease erythropoiesis when Irp1 was ablated in the mice. (D) Serum EPO levels of control diet–fed VhlR200W Irp1–/– mice were 3.3-fold higher than were those of WT mice (data for WT mice are the same as those in Figure 3A). (E) Hematocrit, (F) hemoglobin, and (G) RBC levels of 10-month-old mice on a control diet or Tempol diet after placing them in normoxic or hypoxic (10% oxygen) conditions showed that blood parameters significantly increased in the hypoxic control diet–fed mice and that Tempol supplementation partially prevented erythrocytosis/polycythemia in these mice. *P ≤ 0.05, **P ≤ 0.01, and ***P < 0.001, by 1-way ANOVA.