title: Biased Agonism of the Angiotensin II Type I Receptor.
abstract: Angiotensin II (AngII) type I receptor (AT1R) recognizes AngII, a cardiovascular peptide hormone that acts as a terminal effector of the renin-angiotensin system (RAS). AT1R belongs to the rhodopsin-like peptidergic family of G protein-coupled receptors (GPCRs) and serves as a therapeutic target for the treatment of cardiovascular diseases, such as hypertension, cardiac hypertrophy and heart failure. Classically, AT1R was considered to signal only through G proteins. However, recent studies have revealed that AT1R is capable of activating G protein-independent signaling that is mediated by β-arrestins. β-arrestin is a cytosolic scaffold that is recruited to the activated GPCRs. In vitro and ex vivo studies have demonstrated that the activation of the AT1R-β-arrestin pathway stimulates contractility and exerts prosurvival effects in cardiomyocytes. TRV027, a potent synthetic β-arrestin-biased ligand for AT1R, specifically activates AT1R-β-arrestin signaling without stimulating G proteins. In preclinical studies, TRV027 not only produced vasodilation by antagonizing the AT1R-Gαq pathway but also enhanced cardiac performance by activating AT1R-β-arrestin signaling. Because of this unique pharmacological profile, TRV027 is now being evaluated in a phase II clinical trial as a novel therapeutic for acute heart failure (AHF).
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kumagai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Motozawa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019390:Arrestins; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH