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 hypoxia-inducible factor (HIF)2α 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 idiopathic PAH 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 hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH 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.
Highlights
Oxygen exchange in the lungs requires a fine matching between ventilation and perfusion
Regional lung vasoconstriction stimulates a dynamic shift in perfusion to aid maximal capture of oxygen, prolonged exposure to hypoxia initiates a potent stimulus that leads to pulmonary vascular remodelling that is a hallmark of idiopathic pulmonary fibrosis[2], chronic obstructive pulmonary disease[3] and pulmonary hypertension[4]
We assessed the disruption of HIF2α/ARNT interaction/dimer by co-immunoprecipitation assay in 786-O cells
Summary
Oxygen exchange in the lungs requires a fine matching between ventilation and perfusion. The lungs are exposed to the highest partial oxygen tension in the body, there are physiological and pathological conditions that result in local low oxygen availability (hypoxia). This local hypoxia is counteracted by the exclusive, unique oxygen sensing capability of the pulmonary vasculature characterised by a profound vasoconstrictive response to diminishing oxygen tension[1]. Regional lung vasoconstriction stimulates a dynamic shift in perfusion to aid maximal capture of oxygen, prolonged exposure to hypoxia initiates a potent stimulus that leads to pulmonary vascular remodelling that is a hallmark of idiopathic pulmonary fibrosis[2], chronic obstructive pulmonary disease[3] and pulmonary hypertension[4]. There is, an unmet clinical need to develop novel transformative therapies
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