G protein-coupled receptor kinase 2 contributes to impaired fatty acid metabolism in the failing heart

Journal of Molecular and Cellular Cardiology
Jessica PflegerWalter J Koch

Abstract

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 TgG...Continue Reading

Citations

Jan 10, 2020·Science Translational Medicine·Markus WallnerSteven R Houser
Jan 21, 2021·Cells·Daniela SorrientoGuido Iaccarino
Feb 7, 2021·Journal of Molecular and Cellular Cardiology·Kamila M BledzkaSarah M Schumacher
May 26, 2021·Journal of Internal Medicine·H KorpelaS Ylä-Herttuala
Sep 4, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Satya Murthy TadinadaE Dale Abel

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