{"doi":"10.1182/blood.2020009138","title":"Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases","abstract":"Polycythemia and pulmonary hypertension are 2 human diseases for which better therapies are needed. Upregulation of hypoxia-inducible factor-2α (HIF-2α) 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 VhlR200W mutation. Moreover, the aged VhlR200W mice developed pulmonary fibrosis, most likely due to the increased expression of Cxcl-12, another Hif-2α 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-2α, and the resultant high expression of the Hif-2α targets EPO, endothelin-1, and Cxcl-12. In this study, we inactivated Hif-2α with the second-generation allosteric HIF-2α inhibitor MK-6482 in VhlR200W, Irp1-KO, and double-mutant VhlR200W;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 VhlR200W, Irp1-KO, and VhlR200W;Irp1-KO mice to near normal wild-type levels and normalized the movement of the cardiac interventricular septum in VhlR200Wmice. 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-2α.","journal":"Blood","year":2020,"id":66729,"datarank":0.5926865577872142,"base_score":3.9512437185814275,"endowment":3.9512437185814275,"self_citation_contribution":0.5926865577872142,"citation_network_contribution":0.0,"self_endowment_contribution":0.5926865577872142,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":353510,"name":"Deliang Zhang","orcid":"0000-0002-3712-1776","position":1,"is_corresponding":false},{"id":354787,"name":"Wade H. Ollivierre","orcid":null,"position":2,"is_corresponding":false},{"id":321936,"name":"Audrey Noguchi","orcid":null,"position":3,"is_corresponding":false},{"id":299704,"name":"Danielle Springer","orcid":"0000-0002-6261-9744","position":4,"is_corresponding":false},{"id":51073,"name":"W. Marston Linehan","orcid":"0000-0001-7983-3109","position":5,"is_corresponding":false},{"id":228143,"name":"Tracey A. Rouault","orcid":"0000-0003-0062-0245","position":6,"is_corresponding":false},{"id":251368,"name":"Manik C. Ghosh","orcid":"0000-0002-6461-9545","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:14:50.590588Z","pmid":"33512384","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}