G protein-coupled receptor kinase 2 contributes to impaired fatty acid metabolism in the failing heart
| Autor: | Jessica Pfleger, Rhonda L. Carter, Polina Gross, Walter J. Koch, Steven R. Houser, Erhe Gao, Jaslyn Johnson, Douglas G. Tilley |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
CD36 Antigens
0301 basic medicine medicine.medical_specialty G-Protein-Coupled Receptor Kinase 2 Bioenergetics CD36 Mice Transgenic 030204 cardiovascular system & hematology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Myocytes Cardiac Phosphorylation Receptor Molecular Biology Heart Failure Mice Knockout G protein-coupled receptor kinase Fatty acid metabolism biology Chemistry Kinase Beta adrenergic receptor kinase Fatty Acids Lipid Metabolism Disease Models Animal 030104 developmental biology Endocrinology biology.protein Disease Susceptibility Cardiology and Cardiovascular Medicine Biomarkers |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 123:108-117 |
| ISSN: | 0022-2828 |
| Popis: | Increased G protein-coupled receptor kinase (GRK)2 is central to heart failure (HF) pathogenesis, via desensitization of β-adrenergic receptors and loss of contractile reserve. Since GRK2 has been shown to compromise fatty acid (FA) oxidation, this kinase may link metabolic and contractile defects in HF. The aim of this study was to investigate the mechanistic role of GRK2 in FA metabolism and bioenergetics in the heart. For that purpose, we measured FA uptake and cluster of differentiation (CD)36 expression, phosphorylation, and ubiquitination in mice with cardiac-specific overexpression of GRK2 (TgGRK2) or expression of its c-terminus (GRK2 inhibitor- TgβARKct) or in global heterozygous GRK2 knockout (GRK2+/−) mice. Cellular bioenergetics were also measured in isolated cardiomyocytes following adenoviral delivery of exogenous GRK2, βARKct, or short hairpin GRK2 (shGRK2). Additionally, CD36 expression and phosphorylation were evaluated following transverse aortic constriction (TAC) in wild type (WT) and GRK2+/− mice. Our results show a 33% ± 0.81 reduction in FA uptake rate, accompanied by 51% ± 0.17 lower CD36 protein, and 70% ± 0.23 and 69% ± 0.18 increases in CD36 phosphorylation and ubiquitination, respectively, in the TgGRK2 mice. Moreover, an in vitro kinase assay suggests that GRK2 directly phosphorylates CD36. In isolated cardiomyocytes, GRK2 overexpression induced a 26% ± 2.21 decrease in maximal respiration, which was enhanced (20% ± 4.02–5.14) with inhibition of the kinase. Importantly, in hearts with systolic dysfunction, notable reductions in CD36 mRNA and protein, as well as a significant increase in CD36 phosphorylation were normalized in the GRK2+/− mice post-TAC. Thus, we propose that GRK2 up-regulation in HF is, at least partly, responsible for reduced FA uptake and oxidation and may be a nodal link between metabolic and contractile defects. |
| Databáze: | OpenAIRE |
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