The endothelin (ET) system consists of two G-protein-coupled receptors (ETA and ETB), three peptide ligands (ET-1, ET-2 and ET-3), and two activating peptidases (endothelin-converting enzyme-, ECE-1 and ECE-2). While initially described as a vasoregulatory factor, shown to influence several cardiovascular diseases, from hypertension to heart failure, ET-1, the predominant form in most cells and tissues, has expanded its pathophysiological relevance by recent evidences implicating this factor in the regulation of fibrosis. In this article, we review the current knowledge of the role of ET-1 in the development of fibrosis, with particular focus on the regulation of its biosynthesis and the molecular mechanisms involved in its profibrotic actions. We summarize also the contribution of ET-1 to fibrotic disorders in several organs and tissues. The development and availability of specific ET receptor antagonists have greatly stimulated a number of clinical trials in these pathologies that unfortunately have so far given negative or inconclusive results. This review finally discusses the circumstances underlying these disappointing results, as well as provides basic and clinical researchers with arguments to keep exploring the complex physiology of ET-1 and its therapeutic potential in the process of fibrosis.
Keywords: Endothelin; Endothelin receptor antagonists; Extracellular matrix; Fibrosis.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.