Abstract 075: Novel Role for GRK2 in Cardiac Hypertrophy and Heart Failure

Abstract

During heart failure (HF), cardiac levels and activity of the G protein-coupled receptor (GPCR) kinase (GRK) GRK2 are elevated, increasing phosphorylation, desensitization and down-regulation of β-adrenergic receptors (βARs) and other cardiac GPCRs. Increased GRK2 has been shown to participate in adverse remodeling and contractile dysfunction during HF, while GRK2 inhibition via a carboxy-terminal peptide, βARKct, enhances heart function and can prevent HF development. Mounting evidence supports the idea of a dynamic GRK2 “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several novel GRK2 interacting partners are important for adaptive and maladaptive myocyte growth including Gq, the signaling trigger for maladaptive cardiac hypertrophy, leading to HF. Importantly, GRK2 contains a putative amino-terminal Regulator of G protein Signaling (RGS) domain (termed βARK-RGS). This domain directly interacts with Gq and appears to inhibit signaling without altering Gq enzymatic activity. Therefore, this domain of GRK2 may alter hypertrophic responses in the heart and represent a novel role for GRK2 and also a potential therapeutic target to limit maladaptive cardiac hypertrophy. We have begun to address this by generation of novel transgenic mice with cardiac-specific expression of the RGS domain of GRK2. Data from mice with cardiac expression of βARK-RGS demonstrate anti-hypertrophic effects in a trans-aortic constriction (TAC) model of pressure overload hypertrophy. Echocardiographic analysis post-TAC revealed reduced left ventricular posterior wall thickness in βARK-RGS compared to non-transgenic littermate controls (1.34 vs 1.57 mm LVPWd at 4 weeks). RT-PCR analysis found decreased hypertrophic factor transcripts, such as ANF for which the nearly 18-fold increase post TAC was completely inhibited in βARK-RGS mice. Other hypertrophic phenotypic markers have been studied and mechanistic characterization is underway. These data support our hypothesis that the RGS domain of GRK2 may serve as a non-canonical inhibitor of Gq-mediated hypertrophic signaling in the heart and highlight how this research may pave the way for novel GRK2-based therapeutic approaches to prevent hypertrophy and HF.