Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • For authors
    • Instructions for authors
    • Submit a manuscript
    • Author FAQs
    • Open access
    • COVID-19 submission information
  • Alerts
  • Podcasts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • For authors
    • Instructions for authors
    • Submit a manuscript
    • Author FAQs
    • Open access
    • COVID-19 submission information
  • Alerts
  • Podcasts
  • Subscriptions

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

David Macias, Stephen Moore, Alexi Crosby, Mark Southwood, Xinlin Du, Huiling Tan, Shanhai Xie, Arlette Vassallo, Alex JT Wood, Eli M Wallace, Andrew S Cowburn
European Respiratory Journal 2020; DOI: 10.1183/13993003.02061-2019
David Macias
1CRUK Cambridge Centre Early Detection Programme, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for David Macias
Stephen Moore
2Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexi Crosby
2Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark Southwood
3Department of Pathology, Papworth Hospital National Health Service Foundation Trust, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xinlin Du
4Peloton Therapeutics Inc., Dallas, TX, USA
5A Subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Huiling Tan
4Peloton Therapeutics Inc., Dallas, TX, USA
5A Subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shanhai Xie
4Peloton Therapeutics Inc., Dallas, TX, USA
5A Subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arlette Vassallo
2Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alex JT Wood
2Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eli M Wallace
4Peloton Therapeutics Inc., Dallas, TX, USA
5A Subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew S Cowburn
2Department of Medicine, University of Cambridge, Cambridge, United Kingdom
5A Subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
6National Heart and Lung Institute, Imperial College London, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andrew S Cowburn
  • Article
  • Info & Metrics
  • PDF
Loading

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.

Footnotes

This 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 issued

Conflict of interest: Dr. Tan reports In addition, Dr. Tan has a patent composition for use in treating pulmonary arterial hypertension issued

Conflict of interest: Dr. Xie reports In addition, Dr. Xie has a patent composition for use in treating pulmonary arterial hypertension issued

Conflict 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;.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received October 22, 2019.
  • Accepted August 26, 2020.
  • Copyright ©ERS 2020
http://creativecommons.org/licenses/by/4.0/

This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.

PreviousNext
Back to top
View this article with LENS
Vol 57 Issue 2 Table of Contents
European Respiratory Journal: 57 (2)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension
David Macias, Stephen Moore, Alexi Crosby, Mark Southwood, Xinlin Du, Huiling Tan, Shanhai Xie, Arlette Vassallo, Alex JT Wood, Eli M Wallace, Andrew S Cowburn
European Respiratory Journal Jan 2020, 1902061; DOI: 10.1183/13993003.02061-2019

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension
David Macias, Stephen Moore, Alexi Crosby, Mark Southwood, Xinlin Du, Huiling Tan, Shanhai Xie, Arlette Vassallo, Alex JT Wood, Eli M Wallace, Andrew S Cowburn
European Respiratory Journal Jan 2020, 1902061; DOI: 10.1183/13993003.02061-2019
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Dynamics of SARS-CoV-2 shedding in the respiratory tract depends on the severity of disease in COVID-19 patients
  • Point-of-care lung ultrasound assessment for risk stratification and therapy guiding in COVID-19 patients. A prospective non-interventional study
  • Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease
Show more Original article

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Reviewers
  • CME
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Submit a manuscript
  • ERS author centre

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2021 by the European Respiratory Society