Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases

• Published in: Nature communications 2016-03, Vol.7 (1), p.10877-15, Article 10877
• Main Authors: Cannavo, Alessandro, Liccardo, Daniela, Eguchi, Akito, Elliott, Katherine J., Traynham, Christopher J., Ibetti, Jessica, Eguchi, Satoru, Leosco, Dario, Ferrara, Nicola, Rengo, Giuseppe, Koch, Walter J.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 14; 14/19; 38; 42; 42/35; 59; 631/45/612/1234; 631/45/776/775; 631/80/86; 64; 64/110; 692/699/75; 82; 82/1; 82/29; Aldosterone - toxicity; Animals; Arrestins - genetics; Arrestins - metabolism; beta-Arrestins; Cell Culture Techniques; Cell Movement; G-Protein-Coupled Receptor Kinases - metabolism; Gene Expression Regulation, Enzymologic - physiology; Heart Diseases - chemically induced; Heart Failure - pathology; Humanities and Social Sciences; Humans; Mice; Microscopy, Confocal; multidisciplinary; Muscle Cells - metabolism; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Science; Science (multidisciplinary); Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10877

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 (AT 1 R). 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. High aldosterone levels cause heart damage independently of its well-known effect on blood pressure. Here, Cannavo et al . show that aldosterone-mediated cardiac pathology involves G protein-coupled receptor (GPCR) kinase 2 (GRK2) and GRK5 that integrate signals from angiotensin II receptor (AT1R).