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

Alessandro Cannavo, Daniela Liccardo, Akito Eguchi, Katherine J. Elliott, Christopher J. Traynham, Jessica Ibetti, Satoru Eguchi, D. Leosco, Nicola Ferrara, Giuseppe Rengo, Walter J. Koch

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number10877
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Mar 2 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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    Cannavo, A., Liccardo, D., Eguchi, A., Elliott, K. J., Traynham, C. J., Ibetti, J., Eguchi, S., Leosco, D., Ferrara, N., Rengo, G., & Koch, W. J. (2016). Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nature Communications, 7, [10877]. https://doi.org/10.1038/ncomms10877