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Current and future strategies for targeting the endothelin pathway in cardiovascular disease

Nature Cardiovascular Research volume 2, pages 972–990 (2023)Cite this article

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Abstract

The first endothelin (ET)-1 receptor antagonist was approved for clinical use over 20 years ago, but to date this class of compounds has been limited to treating pulmonary arterial hypertension, a rare disease. Translational research over the last 5 years has reignited interest in the ET system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-coronavirus disease 2019 conditions. Notable developments include approval of a new ETA receptor antagonist and, intriguingly, combining the actions of ETA and an angiotensin II type 1 receptor antagonist within the same novel small molecule. Combinations of ET receptor blockers with other drugs, including phosphodiesterase-5 inhibitors and sodium–glucose co-transporter-2 antagonists, may drive synergistic benefits with the prospect of alleviating side effects. These new therapeutic strategies have the potential to dramatically widen the scope of indications targeting the ET-1 pathway.

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Fig. 1: Synthesis of endogenous ET peptides.
Fig. 2: Therapeutic targets of approved and investigational ET antagonists in the human vasculature.
Fig. 3: Expression of EDN1 mRNA in human endothelial cells and unusual pharmacological properties of the peptide.
Fig. 4: Timeline of key discoveries in the ET-1 signaling pathway and identification of selective therapeutic agents.
Fig. 5: Hypothesized mechanism for increased plasma ET-1 levels observed in severe COVID-19 infection.
Fig. 6: Selectivity of ET compounds.

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Acknowledgements

The authors are grateful for the following support: The Jon Moulton Charity Trust (to G.R.A. and A.P.D.); National Institute of Health Research, Cambridge Biomedical Research Centre (BRC-1215-20014; to A.P.D.); Biomedical Resources Grant, University of Cambridge (Cardiovascular Theme RG64226; to A.P.D.); British Heart Foundation (TG/18/4/33770; to A.P.D. and J.J.M.). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. We thank CMC Connect (a division of IPG Health Medical Communications) funded by AstraZeneca who, under the direction of the authors, carried out a search of clinical trials, formatted text, diagrams and references.

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Authors and Affiliations

  1. Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    George R. Abraham, Thomas L. Williams, Janet J. Maguire & Anthony P. Davenport

  2. Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

    George R. Abraham

  3. Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Peter J. Greasley

  4. Late-Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Philip Ambery

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G.R.A., T.L.W. and J.J.M. declare no competing interests. P.J.G. and P.A. are employees of AstraZeneca (UK). A.P.D. is a co-investigator for the Medical Research Council PRIZE trial and a member of the scientific advisory boards of Janssen, ENB Therapeutics and Pharmazz.

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Abraham, G.R., Williams, T.L., Maguire, J.J. et al. Current and future strategies for targeting the endothelin pathway in cardiovascular disease. Nat Cardiovasc Res 2, 972–990 (2023). https://doi.org/10.1038/s44161-023-00347-2

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