Abstract 1250: Loss Of G Protein-coupled Receptor Kinase 2 (grk2) In Cardiac Myocytes Protects Against Structural Heart Disease
We have previously shown that G protein-coupled receptor kinase 2 (GRK2 or BARK1) is a critical regulator of cardiac beta-adrenergic receptor (BAR) signaling and cardiac function. Inhibition of the membrane translocation of GRK2 by expression of the BARKct peptide can rescue disparate models of heart failure (HF) and we remain interested to determine if loss of GRK2 expression, which is up-regulated in failing myocardium, also is therapeutic. Non-targeted deletion of the GRK2 gene in mice results in embryonic lethality. To overcome this limitation we have generated mice with cardiac-specific knockout of GRK2 using the Cre/LoxP system, which produced viable mice that survived into adulthood. Cardiac-specific knockout of GRK2 in the adult heart (MHC-Cre/GRK2(fl/fl) mice) prior to myocardial infarction (MI) prevented cardiac hypertrophy, left ventricular dilatation and dysfunction. Tamoxifen-induced cardiac-specific knockout of GRK2 (MerCreMer/GRK2(fl/fl) mice) in the failing heart after MI improved survival (p=0.004) and rescued the HF phenotype. The reversal of cardiac dysfunction after the loss of GRK2 expression was via enhanced cardiac function and LV remodeling. On the cellular level, diastolic [Ca2+]i levels in failing MHC-Cre/GRK2(fl/fl) cardiac myocytes were decreased to levels seen in cardiomyocytes from SHAM mice. In addition, peak Ca2+-transients were significantly augmented, which inhibited the attenuation of contractile performance in cardiomyocytes isolated from infarcted hearts. These findings were accompanied by a lower SR-Ca load and an increased L-type Ca-current in control KO mice. Our findings mark GRK2 as a determinant of clinically important heart disease phenotypes, and suggest GRK2 inhibition as a highly selective approach for targeting adverse cardiac remodeling in the failing heart.