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Endothelins in cardiovascular biology and therapeutics

Nature Reviews Cardiology volume 16, pages 491–502 (2019)Cite this article

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Abstract

Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors — endothelin receptor type A (ETA) and endothelin receptor type B (ETB) — with equal affinity, whereas ET-3 has a lower affinity for ETA. ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ETB) and possibly signalling pathway-biased agonists and antagonists.

Key points

  • Endothelin 1 (ET-1) is the most potent endogenous vasoconstrictor and contributes to basal vascular tone as well as a number of diseases, such as hypertension, chronic kidney disease (CKD), pulmonary arterial hypertension (PAH) and pre-eclampsia.

  • A common non-coding gene sequence variant regulates the expression of EDN1 (encoding ET-1) and is linked to five common vascular conditions: coronary artery disease, hypertension, migraine, cervical artery dissection and fibromuscular hyperplasia.

  • The effects of ET-1 are mediated via two G protein-coupled receptors, endothelin receptor type A (ETA) and endothelin receptor type B (ETB); selective ETA and dual ETA/ETB receptor antagonists (endothelin receptor antagonists; ERAs) are available for clinical use.

  • The phase III PRECISION study will explore the use of a long-acting, selective ETA antagonist in treatment-resistant hypertension.

  • For many patients with PAH, ERAs are considered first-line treatment; ERAs also reduce blood pressure and proteinuria in CKD and show clinical potential in scleroderma renal crisis, the transition from acute kidney injury to CKD and end-stage renal disease.

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Fig. 1: Endothelin 1 synthesis and sites of action.
Fig. 2: Endothelin receptor mRNA expression in different organs.
Fig. 3: Effects of endothelin 1 in the kidney.

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Acknowledgements

N.D. has research funding from the Medical Research Council to explore the role of the endothelin system in kidney disease (MRC ref: 6152177 I181211-0759).

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Nature Reviews Cardiology thanks E. Schiffrin and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. University of Edinburgh/British Heart Foundation Centre of Research Excellence, Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK

    Neeraj Dhaun & David J. Webb

  2. Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK

    Neeraj Dhaun

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  1. Neeraj Dhaun
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Both authors researched data for the article, discussed its content and wrote the manuscript. D.J.W. reviewed and edited the manuscript before submission.

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Correspondence to Neeraj Dhaun.

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Competing interests

N.D. has acted as a consultant for Retrophin. D.J.W. is a member of an Independent Data Monitoring Committee for a trial with AbbVie of atrasentan in diabetic renal disease and is the UK Chief Investigator for a trial with Idorsia of aprocitentan in treatment-resistant hypertension.

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Dhaun, N., Webb, D.J. Endothelins in cardiovascular biology and therapeutics. Nat Rev Cardiol 16, 491–502 (2019). https://doi.org/10.1038/s41569-019-0176-3

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