Open AccessPharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure
Author(s) -
Ciccarelli Michele,
Sorriento Daniela,
Fiordelisi Antonella,
Gambardella Jessica,
Franco Antonietta,
Giudice Carmine,
Sala Marina,
Monti Maria Gaia,
Bertamino Alessia,
Campiglia Pietro,
Oliveti Marco,
Poggio Paolo,
Trinchese Giovanna,
Cavaliere Gina,
Cipolletta Ersilia,
Mollica Maria Pina,
Bonaduce Domenico,
Trimarco Bruno,
Iaccarino Guido
Publication year - 2020
Publication title -
esc heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.787
H-Index - 25
ISSN - 2055-5822
DOI - 10.1002/ehf2.12706
Subject(s) - heart failure , contractility , cardiac function curve , ventricle , medicine , beta adrenergic receptor kinase , myocyte , in vivo , cardiology , myocardial infarction , endocrinology , pharmacology , biology , receptor , microbiology and biotechnology , g protein coupled receptor
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.