Abstract 109: G Protein-coupled Receptor Kinase 2 Impairs Fatty Acid Metabolism in the Failing Heart Through Novel Mechanisms

Compromised contractility and energetics are hallmarks of the failing heart. Increased G protein-coupled receptor kinase (GRK)2 is central to the pathogenesis of heart failure (HF), via desensitization of beta-adrenergic receptors and, therefore, loss of contractile reserve. Additionally, we, and others, have reported that GRK2 has non-canonical activity that contributes to its pathological functionality in HF. For example, GRK2 can compromise fatty acid (FA) metabolism in cardiomyocytes, the mechanism of which remains unknown. Thus, our aim is to investigate the role of GRK2 in FA metabolism and bioenergetics in the heart. To do this, we measured FA uptake, cluster of differentiation (CD)36 expression, phosphorylation, and ubiquitination, and FA-driven bioenergetics in mice with cardiac-specific overexpression of GRK2, to levels observed in the human failing myocardium, or a GRK2 inhibitory peptide (TgGRK2 and TgβARKct, respectively) or in global heterozygous GRK2 knockout (GRK2 ) mice. Additionally, we determined CD36 expression and phosphorylation following cardiac dysfunction induced by transverse aortic constriction (TAC). The results show a significant reduction in FA uptake rates (0.3-fold) and CD36 protein (0.8-fold), which was associated with an increase in its phospho-serine/threonine (0.7-fold increase) and ubiquitin-lysine (0.7-fold) content in the TgGRK2 mice. In contrast, these parameters were unchanged in the TgβARKct or GRK2 mice. A reduction in CD36 mRNA (0.7-fold) and protein levels (0.2-fold) were detected in post-TAC, failing hearts, which was associated with an increase is its phosphorylation (0.5-fold). Notably, normalization of CD36 protein levels is observed in GRK2 mice post-TAC. Maximal respiratory capacity was also enhanced in TgβARKct and GRK2 cardiomyocytes (0.6- and 0.8-fold, respectively). Together, our results show that up-regulation of GRK2 induces CD36 phosphorylation, ubiquitination, and downregulation, which is associated with reduced FA uptake. Thus, we propose that the increase in GRK2 observed during HF is, at least partly, responsible for reduced FA uptake and oxidation and may be an important nodal switch in substrate utilization during HF pathogenesis.

Duke Scholars

Author Walter J. Koch Surgery, Cardiovascular and Thoracic Surgery