Abstract 600: Inhibition of G Protein-Coupled Receptor Kinase-3 (GRK3) Rescues Cardiac Dysfunction after Pressure Overload

Abstract

Background: Previous studies of transgenic mice with cardiac-restricted inhibition of G protein-coupled receptor kinase-3 (GRK3) have disclosed phenotype consistent with α 1 - adrenergic receptor (α 1 -AR) hyperresponsiveness. As opposed to GRK2 (β-ARK1), an isoenzyme with selectivity for β-AR, the pathophysiologic role of GRK3 in heart failure has not been investigated. Accordingly, the functional role of GRK3 during evolving cardiac dysfunction after pressure overload was dissected in this study. Methods and results: GRK3ct transgenic mice (Tg-GRK3ct) with α-MHC promoter-driven expression of mini-gene encoding the carboxyl-terminal membrane targeting domain of GRK3 were employed. Inhibition of endogenous GRK3 was confirmed by enhanced α 1 -AR mediated activation of ERK 1/2 in cardiac myocytes from Tg-GRK3ct as compared to non-transgenic littermates controls (NLC). Tg-GRK3ct mice characteristically displayed myocardial hypercontractility despite unaltered cardiac mass, compared to NLC. Pressure overload was induced by abdominal aortic banding (AB) in weight matched male Tg-GRK3ct (GRK3ct-AB) and NLC (NLC-AB) mice and compared with sham-operated Tg-GRK3ct (GRK3ct-SH) and NLC (NLC-SH) mice. Echocardiography disclosed similar baseline cardiac dimensions among all groups. Eight and twelve weeks after AB significant increases of cardiac mass were found in AB mice compared to sham, but no differences between GRK3ct-AB and NLC-AB were discerned. Eight weeks after AB, analysis of electrically paced, ex vivo perfused hearts at increasing filling pressures revealed preserved end-diastolic and end-systolic pressure-volume (PV) relations in GRK3ct-AB (n=10), with substantially higher cardiac output and dP/dt max compared to NLC-AB (n=10). Twelve weeks after AB, simultaneous in vivo PV-analysis revealed elevated end-diastolic pressure (10.6±3.1 mmHg vs. 2.7±2.2, p<0.05) and lower cardiac output (7379±738 μL/min vs. 9847±785, p<0.05) in NLC-AB (n=11) compared to GRK3ct-AB (n=16). Consistently, myocardial mRNA level of B-type natriuretic peptide was substantially elevated in NLC-AB compared to GRK3ct-AB (p<0.05). Conclusion: Inhibition of cardiac GRK3 in mice rescues cardiac dysfunction and heart failure after pressure overload.