Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

By Andrew Cowburn

In a paper just accepted for publication in Eur Respir J, we investigated the impact of a novel small molecule inhibitor that targets HIF2α-ARNT hetero-dimerisation as a potential therapeutic strategy for pulmonary hypertension.

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. All current therapeutic intervention strategies only slow disease progression. Recently the aberrant expression of hypoxia-inducible factor (HIF)2α in pulmonary vascular lesions has been associated with PAH disease severity. 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. We report that global inhibition of HIF2α reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention pre-clinical models. We show how inhibition of HIF2α restored the expression of key gene targets, reduced circulating pro-inflammatory factors and returned plasma nitrites to near-normal levels.

Treatment of monocrotaline exposed rodents (second pre-clinical model) 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-dimerization 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.

References

1. Macias D, Moore S, Crosby A, et al. Targeting HIF2α-ARNT hetero- dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.02061-2019).