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Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure
Michele Ciccarelli1, Daniela Sorriento2, Antonella Fiordelisi2
1Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi, Italy.
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.
Insights
Pharmacological inhibition of GRK2 (G protein-coupled receptor kinase 2) using C7 peptide improves cardiac metabolism and function in heart failure (HF) models. This targeted approach corrects metabolic and contractile abnormalities in the failing heart.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Heart failure (HF) involves significant alterations in myocardial metabolism.
- The role of GRK2 (G protein-coupled receptor kinase 2) in regulating cardiac metabolism during HF is not well understood.
- GRK2 is a key regulator of G protein-coupled receptor signaling in the heart.
Purpose of the Study:
- To investigate the effects of GRK2 inhibition on myocardial metabolism in experimental heart failure.
- To evaluate the therapeutic potential of a novel GRK2 inhibitor, C7, in a mouse model of HF.
- To assess the impact of C7 on metabolic, biochemical, and functional parameters in the failing heart.
Main Methods:
- Pharmacological inhibition of GRK2 using a cyclic peptide (C7) in vitro and in vivo.
- Assessment of C7 selectivity in wild-type and GRK2-deficient mouse ventricular myocytes.
- Induction of chronic heart failure in mice via cryogenic myocardial infarction.
- Evaluation of cardiac function using echocardiography and cardiac catheterization.
- Histological, biochemical, and metabolic analyses of heart tissues.
Main Results:
- C7 demonstrated selective inhibition of GRK2, enhancing contractility in wild-type but not GRK2-deficient myocytes.
- Chronic C7 treatment in HF mice improved mitochondrial organization and function.
- C7 administration restored biochemical and contractile responses in the failing heart.
- Metabolic features in HF mice were significantly improved by C7 treatment.
Conclusions:
- GRK2 plays a critical role in the physiological regulation of cardiac metabolism.
- Pharmacological targeting of GRK2 in HF can correct metabolic and functional abnormalities.
- C7 represents a promising therapeutic strategy for managing heart failure by modulating cardiac metabolism.
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