Key Points Transient BM transplant reverses disease in Hmox1−/− mouse by repopulating tissues with wild-type macrophages capable of recycling heme. Established donor macrophage populations remain functionally and quantitatively persistent without additional input from hematopoietic tissue.

Polycythemia and pulmonary hypertension are two human diseases for which better therapies are needed. Upregulation of hypoxia inducible factor2α (HIF2α) and its target genes, erythropoietin (EPO) and endothelin-1 causes polycythemia and pulmonary hypertension in Chuvash polycythemia patients who are homozygous for R200W mutation in the von Hippel Lindau (VHL) gene, and in a murine mouse model of Chuvash polycythemia that bears the same homozygous VhlR200W mutation. Moreover, the aged VhlR200Wmice developed pulmonary fibrosis likely due to the increased expression of Cxcl12, another Hif2α 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 de-repression of Hif2α, and resultant high expression of Hif2α targets EPO, endothelin-1 and Cxcl12. Here, we inactivated Hif2α with the second-generation allosteric HIF2α inhibitor, MK-6482 in VhlR200W mice, Irp1-KO mice, and double mutant VhlR200W; Irp1-KO mice. MK-6482 treatment decreased EPO production and reversed polycythemia in all three mouse models. Drug treatment also decreased the right ventricular pressures and mitigated pulmonary hypertension in VhlR200Wmice, Irp1-KO mice, and VhlR200W;Irp1-KO mice to near normal WT levels, and normalized the movement of the cardiac interventricular septum in VhlR200Wmice. MK-6482 treatment reduced the increased expression of Cxcl12, which in association with CXCR4 mediates fibrocyte influx to 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 HIF2α.