@article {Macias1902061, author = {David Macias and Stephen Moore and Alexi Crosby and Mark Southwood and Xinlin Du and Huiling Tan and Shanhai Xie and Arlette Vassallo and Alex JT Wood and Eli M Wallace and Andrew S Cowburn}, title = {Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension}, elocation-id = {1902061}, year = {2020}, doi = {10.1183/13993003.02061-2019}, publisher = {European Respiratory Society}, abstract = {Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Macias has nothing to disclose.Conflict of interest: Dr. Moore has nothing to disclose.Conflict of interest: Dr. Crosby has nothing to disclose.Conflict of interest: Dr. Southwood has nothing to disclose.Conflict of interest: Dr. Du reports In addition, Dr. Du has a patent~composition for use in treating pulmonary arterial hypertension issuedConflict of interest: Dr. Tan reports In addition, Dr. Tan has a patent composition for use in treating pulmonary arterial hypertension issuedConflict of interest: Dr. Xie reports In addition, Dr. Xie has a patent~composition for use in treating pulmonary arterial hypertension issuedConflict of interest: Dr. Vassallo has nothing to disclose.Conflict of interest: Dr. Wood has nothing to disclose.Conflict of interest: Dr. Wallace reports In addition, Dr. Wallace has a patent Compositions for use in treating pulmonary arterial hypertension issued.Conflict of interest: Dr. Cowburn reports grants from Peloton Therapeutics Inc, during the conduct of the study;.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/early/2020/08/28/13993003.02061-2019}, eprint = {https://erj.ersjournals.com/content/early/2020/08/28/13993003.02061-2019.full.pdf}, journal = {European Respiratory Journal} }