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      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.

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      Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
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          A novel potent vasoconstrictor peptide produced by vascular endothelial cells.

          An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.

            Author and article information

            Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
            Author notes
            Address correspondence to: Anthony P. Davenport, Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. E-mail: apd10@

            A.P.D. and K.A.H. contributed equally to this work.

            Role: ASSOCIATE EDITOR
            Pharmacol Rev
            Pharmacol. Rev
            Pharmacol Rev
            Pharmacological Reviews
            The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
            April 2016
            April 2016
            April 2016
            : 68
            : 2
            : 357-418
            (ASSOCIATE EDITOR)
            Copyright © 2016 The Author(s)

            This is an open access article distributed under the CC-BY Attribution 4.0 International license.

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