br Clinical potential of ET receptor biased ligands Is
Clinical potential of ET receptor biased ligands Is there a clinical need for ET receptor biased ligands? Evidence is strongest from research in epithelial ovarian cancer demonstrating that ET-1 stimulated ETA-mediated β-arrestin signalling leads to activation of the oncogenic mediator NF-κB  and that β-arrestin-1 epigenetically regulates ET-1-induced β-catenin signalling ,  both contributing to tumour cell proliferation, invasion and metastasis. A β-arrestin biased ETA antagonist would be predicted to have benefit over a non-biased ETA antagonist in ovarian cancer as ETA/Gαs/cAMP activation of protein kinase A opposes the detrimental ETA/β-arrestin stimulated expression of cancer genes. ETA/Gq signalling is also oncogenic therefore an alternative strategy that may demonstrate even greater target refinement would be to develop an ETA/Gαs biased agonist as proposed by Teoh and colleagues  (Fig. 2). Interestingly, pepducins have been designed for the β2-adrenoreceptor that selectively promote a Gαs biased conformation  therefore this may be one strategy that can be applied to biased targeting of the ETA receptor in cancer. Could selective activation or inhibition of ET signalling pathways in heart failure result in clinically efficacious drugs and explain the lack of benefit of endothelin receptor antagonists in heart failure clinical trials to date, despite promising evidence from pre-clinical studies? For the angiotensin-II system it has been demonstrated that β-arrestin mediated signalling in heart failure is beneficial and selective activation of this pathway using TRV027 (and thus inhibition of G-protein signalling) promotes both vasodilatation and improved cardiac function at least in animal models . This Indirubin is currently being investigated in a Phase IIb study in patients hospitalised for acute decompensated heart failure (ClinialTrials.gov identifier NCT01966601) with estimated completion March 2016. Conversely, β-arrestin signalling in cardiac fibroblasts has been proposed to contribute to detrimental ventricular remodelling . It is not known if ET receptor mediated β-arrestin signalling is protective in heart failure, but if so it could be inferred that currently available endothelin antagonists that block G-protein and β-arrestin signalling or bosentan that may be a β-arrestin biased antagonist would not produce clinical benefit and may even be detrimental. However, the lack of efficacy in heart failure trials was predominantly owing to the development of peripheral oedema, thought to be a result of effects on endothelin mediated renal salt and water homeostasis rather than a lack of beneficial effect on haemodynamics . It has also been suggested that the contribution of increased ET-1 to pathological cardiac remodelling in heart failure may be a result of ETA mediated inhibition of reuptake of noradrenaline released from cardiac sympathetic nerves . Consequently endothelin antagonists would not confer additional advantage in patients already taking β-blockers enrolled in these trials. Whether the beneficial and detrimental actions of endothelin antagonists in heart failure or other conditions such as hypertension could be discerned by the development of ligands with a particular signalling profile remains mere speculation at this time but should be investigated as the field matures.
Acknowledgements This study was supported by the Wellcome Trust (grant number WT107715). We thank Papworth Hospital NHS Trust Tissue Bank for assistance.
Introduction Angiotensin II (Ang II) and Endothelin 1 (ET-1) are potent vasoconstrictive peptides recognized as key players in many cardiovascular diseases . Cardiac hypertrophy, ischemic arrhythmia, and stroke have been associated to an overstimulation of the angiotensin II type 1 (AT1) receptor . Other diseases like atherosclerosis, and pulmonary hypertension have been associated to an increase in ET-1 synthesis and the consequent overactivation of endothelin 1 type A (ETA) receptors . Additionally, activation of both receptors lead to hypertension, chronic heart failure and renal diseases .