Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases

Polycythemia and pulmonary hypertension are 2 human diseases for which better therapies are needed. Upregulation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) and its target genes, erythropoietin (EPO) and endothelin-1, causes polycythemia and pulmonary hypertension in patients with Chuvash polycythemia who are homozygous for the R200W mutation in the von Hippel Lindau (VHL) gene and in a murine mouse model of Chuvash polycythemia that bears the same homozygous Vhl(R200W) mutation. Moreover, the aged Vhl(R200W) mice developed pulmonary fibrosis, most likely due to the increased expression of Cxcl-12, another Hif-2 alpha target. Patients with mutations in iron regulatory protein 1 (IRP1) also develop polycythemia, and Irp1-knockout (Irp1-KO) mice exhibit polycythemia, pulmonary hypertension, and cardiac fibrosis attributable to translational derepression of Hif-2 alpha, and the resultant high expression of the Hif-2 alpha targets EPO, endothelin-1, and Cxcl-12. In this study, we inactivated Hif-2 alpha with the second-generation allosteric HIF-2 alpha inhibitor MK-6482 in Vhl(R200W), Irp1-KO, and double-mutant Vhl(R200W);Irp1-KO mice. MK-6482 treatment decreased EPO production and reversed polycythemia in all 3 mouse models. Drug treatment also decreased right ventricular pressure and mitigated pulmonary hypertension in Vhl(R200W), Irp1-KO, and Vhl(R200W);Irp1-KO mice to near normal wild-type levels and normalized the movement of the cardiac interventricular septum in Vhl(R200W)mice. MK-6482 treatment reduced the increased expression of Cxcl-12, which, in association with CXCR4, mediates fibrocyte influx into the lungs, potentially causing pulmonary fibrosis. Our results suggest that oral intake of MK-6482 could represent a new approach to treatment of patients with polycythemia, pulmonary hypertension, pulmonary fibrosis, and complications caused by elevated expression of HIF-2 alpha.