title: Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases.
abstract: Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation by aldosterone leads to pathological myocardial signalling mediated by mitochondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic action. Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve cross-talk with the angiotensin II type-1 receptor (AT1R). Most importantly, we show that ventricular dysfunction caused by chronic hyper-aldosteronism in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 KO mice. However, aldosterone-induced cardiac hypertrophy is totally prevented in Grk5 KO mice. We also show human data consistent with MR activation status in heart failure influencing GRK2 levels. Therefore, our study uncovers GRKs as targets for ameliorating pathological cardiac effects associated with high-aldosterone levels.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Liccardo
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Akito
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Elliott
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Traynham
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibetti
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Translational Medical Science, University of Naples Federico II, Via Pansini, 5, Naples 80131, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
authors.affiliation: Department of Translational Medical Science, University of Naples Federico II, Via Pansini, 5, Naples 80131, Italy.|Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme,Via bagni vecchi, 1, Telese Terme, Benevento 82037, Italy.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0001-8200-4942
authors.initials: N
authors.lastname: Ferrara
authors.affiliation: Department of Translational Medical Science, University of Naples Federico II, Via Pansini, 5, Naples 80131, Italy.|Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme,Via bagni vecchi, 1, Telese Terme, Benevento 82037, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000450:Aldosterone / Q000633:toxicity*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D002465:Cell Movement; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006331:Heart Diseases / Q000139:chemically induced*; D006333:Heart Failure / Q000473:pathology; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D032342:Muscle Cells / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D000450:Aldosterone; D054768:G-Protein-Coupled Receptor Kinases