Endothelins in cardiovascular biology and therapeutics

• Published in: Nature reviews cardiology 2019-08, Vol.16 (8), p.491-502
• Main Authors: Dhaun, Neeraj, Webb, David J.
• Format: Article
• Language: English
• Subjects: 692/4019/592/75; 692/699/1585; Angiogenesis Inhibitors - therapeutic use; Animals; Biological Products - therapeutic use; Cardiac Imaging; Cardiac Surgery; Cardiology; Cardiovascular Agents - therapeutic use; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - physiopathology; Cardiovascular System - physiopathology; Care and treatment; Chronic illnesses; Development and progression; Endothelin; Endothelins - physiology; Gene expression; Genetic aspects; Health aspects; Humans; Kidney diseases; Medicine; Medicine & Public Health; Pulmonary hypertension; Review Article; Vasoconstriction
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/s41569-019-0176-3

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 (ET A ) and endothelin receptor type B (ET B ) — with equal affinity, whereas ET-3 has a lower affinity for ET A . 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 ET B ) and possibly signalling pathway-biased agonists and antagonists. Endothelin 1 is the most potent vasoconstrictor in the human cardiovascular system. In this Review, Dhaun and Webb discuss the biology of the endothelins and endothelin receptors and how these pathways can be therapeutically targeted in cardiovascular and renal diseases. 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 (ET A ) and endothelin receptor type B (ET B ); selective ET A and dual ET A /ET B receptor antagonists (endothelin receptor antagonists; ERAs) are available for clinical use. The p