Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure

Michele Ciccarelli, Daniela Sorriento, Antonella Fiordelisi, Jessica Gambardella, Antonietta Franco, Carmine del Giudice, Marina Sala, Maria Gaia Monti, Alessia Bertamino, Pietro Campiglia, Marco Oliveti, Paolo Poggio, Giovanna Trinchese, Gina Cavaliere, Ersilia Cipolletta, Maria Pina Mollica, Domenico Bonaduce, Bruno Trimarco, Guido Iaccarino

Research output: Contribution to journalArticle

Abstract

Aims: The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF. Methods and results: C7 was initially tested on adult mice ventricular myocyte from wild type and GRK2 myocardial deficient mice (GRK2-cKO), to assess the selectivity on GRK2 inhibition. Then, chronic infusion of 2 mg/kg/day of C7 was performed in HF mice with cryogenic myocardial infarction. Cardiac function in vivo was assessed by echocardiography and cardiac catheterization. Histological, biochemical, and metabolic studies were performed on heart samples at time points. C7 induces a significant increase of contractility in wild type but not in adult ventricle myocytes from GRK2-cKO mice, thus confirming C7 selectivity for GRK2. In HF mice, 4 weeks of treatment with C7 improved metabolic features, including mitochondrial organization and function, and restored the biochemical and contractile responses. Conclusions: GRK2 is a critical molecule in the physiological regulation of cardiac metabolism. Its alterations in the failing heart can be pharmacologically targeted, leading to the correction of metabolic and functional abnormalities observed in HF.

Original languageEnglish
Pages (from-to)1571-1584
Number of pages14
JournalESC Heart Failure
Volume7
Issue number4
DOIs
StatePublished - Aug 1 2020

Keywords

  • Adrenergic
  • Beta
  • Hypertrophy
  • Metabolism
  • Mitochondria
  • Remodelling

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