| First Author | Ghosh MC | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 4 | Pages | 1317-1325 |
| PubMed ID | 29480820 | Mgi Jnum | J:261174 |
| Mgi Id | MGI:6154493 | Doi | 10.1172/JCI97684 |
| Citation | Ghosh MC, et al. (2018) Translational repression of HIF2alpha expression in mice with Chuvash polycythemia reverses polycythemia. J Clin Invest 128(4):1317-1325 |
| abstractText | Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2alpha, 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 Hif2alpha, 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 Hif2alpha 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 Hif2alpha expression and markedly reduced life-threatening erythrocytosis/polycythemia in the VhlR200W mice. |
