title: Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor.
abstract: Hyperactivity of the renin-angiotensin-aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin-angiotensin-aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1-7) in AT1-R-expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1-7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin-angiotensin-aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1-7) a known Mas receptor-specific ligand, as an AT1-R-biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1-7) at AT1-R, similar to that of synthetic AT1-R-biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1-7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1-7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin-angiotensin-aldosterone system.
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Galandrin
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Denis
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Boularan
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Marie
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: M'Kadmi
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pilette
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubroca
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Nicaise
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Seguelas
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Du
authors.initials: D
authors.lastname: N'Guyen
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Banères
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Atul
authors.initials: A
authors.lastname: Pathak
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sénard
authors.affiliation: From the Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM, UMR 1048, Université de Toulouse, France (S.G., C.D., C.B., M.-H.S., D.N., A.P., J.-M.S., C.G.); Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, Montpellier Cedex 05, France (J.M., C.M., J.-L.B.); Cardiomedex SAS, Toulouse, France (C.P., C.D.); and Département d'histopathologie (Y.N.) and Service de Pharmacologie Clinique, Faculté de médecine (D.N., A.P., J.-M.S.), Centre Hospitalier Universitaire de Toulouse, France. celine.gales@inserm.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009132:Muscles; D010446:Peptide Fragments / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D010446:Peptide Fragments; D044139:Receptor, Angiotensin, Type 2; D000071557:beta-Arrestins; D000804:Angiotensin II; D010656:Phenylephrine; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: G-protein–coupled receptor; angiotensin 1-7; angiotensin II type 1 receptor; biased agonism; renin–angiotensin system; β-arrestin