TY - JOUR
T1 - Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure
AU - Ciccarelli, Michele
AU - Sorriento, Daniela
AU - Fiordelisi, Antonella
AU - Gambardella, Jessica
AU - Franco, Antonietta
AU - del Giudice, Carmine
AU - Sala, Marina
AU - Monti, Maria Gaia
AU - Bertamino, Alessia
AU - Campiglia, Pietro
AU - Oliveti, Marco
AU - Poggio, Paolo
AU - Trinchese, Giovanna
AU - Cavaliere, Gina
AU - Cipolletta, Ersilia
AU - Mollica, Maria Pina
AU - Bonaduce, Domenico
AU - Trimarco, Bruno
AU - Iaccarino, Guido
N1 - Funding Information:
This work was in part supported by grants from Italian Ministry of Instruction, University and Research (PRIN 2017 and PON Campania Bioscience PON03PE0006008 to G. I.), POR MOVIE from Regione Campania Rete di Biotecnologie (G. I.), University of Salerno's Funds for Basic Research (FARB to G. I. and M. C.), and Italian Society of Hypertension (SIIA to G. I.).
Publisher Copyright:
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - Adrenergic
KW - Beta
KW - Hypertrophy
KW - Metabolism
KW - Mitochondria
KW - Remodelling
UR - http://www.scopus.com/inward/record.url?scp=85084219028&partnerID=8YFLogxK
U2 - 10.1002/ehf2.12706
DO - 10.1002/ehf2.12706
M3 - Article
C2 - 32352228
AN - SCOPUS:85084219028
SN - 2055-5822
VL - 7
SP - 1571
EP - 1584
JO - ESC Heart Failure
JF - ESC Heart Failure
IS - 4
ER -