Abstract
The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
Highlights
The vasoconstrictor actions of a factor obtained from the culture media of bovine aortic endothelial cells was first characterized in 1985 by Hickey et al (1985) and was proposed to have the chemical composition of a peptide, because trypsin abolished the observed activity
In the right ventricle of human hearts from pulmonary arterial hypertension (PAH) patients, there was a significant increase in the ratio of ETA-selective antagonist atrasentan (ETA) to endothelin B receptor (ETB) receptors compared with normal hearts as well as a significant increase in the medial layer of small pulmonary arteries
A cell penetrating peptides (CPP) has been reported for the ETB receptor incorporating an amino acid sequence based on the second intracellular loop of ETB linked to a SynB3 vector derived from the antimicrobial protein protegrin1 (Green et al, 2013)
Summary
Receptor subtypes were characterized by their rank order of affinity for the three ET peptides: ETA: ET-1 = ET=2. The rationale for the study was that stimulating ETB receptors would cause vasodilatation to increase the penetration of cytotoxic antitumor agents into tumors but reduce the concentration in healthy tissue. This hypothesis was based on the reports that IRL1620 increased effectiveness of antitumor agents in rat models of prostrate and breast cancer (Rajeshkumar et al, 2005) as well as improving the efficacy of radiotherapy (Gulati et al, 2012). The complementary approach of ETA antagonism has been suggested as potential benefit in these models (Patel et al, 1996)
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