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

Details

• Alternative Title:
  Nat Commun
• Personal Author:
  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.
• Description:
  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.
• Subjects:
  Aldosterone Animals Arrestins Cell Culture Techniques Cell Movement G-Protein-Coupled Receptor Kinases Gene Expression Regulation, Enzymologic Heart Diseases Heart Failure Humans Mice Microscopy, Confocal Muscle Cells Receptor, Angiotensin, Type 1 Signal Transduction

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• Source:
  Nat Commun. 2016; 7.
• Pubmed ID:
  26932512
• Pubmed Central ID:
  PMC4778065
• Document Type:
  Journal Article
• Funding:
  HL128324/HL/NHLBI NIH HHS/United States ; P01 HK091799/HK/PHITPO CDC HHS/United States ; P01 HL075443/HL/NHLBI NIH HHS/United States ; P01 HL08806/HL/NHLBI NIH HHS/United States ; R01 HL088503/HL/NHLBI NIH HHS/United States ; R37 HL061690/HL/NHLBI NIH HHS/United States
• Volume:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0266cb2d9cfb62a443291ab4c9ccfa17db09d0362b0ccd35f8db03cb5341c512
• Download URL:
  https://stacks.cdc.gov/view/cdc/41034/cdc_41034_DS1.pdf
• File Type:
  [PDF - 2.42 MB ]