Abstract 365: Domain-specific Roles for GRK2 in Cardiac Hypertrophy and Heart Failure
During heart failure (HF), cardiac levels and activity of the G protein-coupled receptor (GPCR) kinase (GRK) GRK2 are elevated and contribute to adverse remodeling and contractile dysfunction, while inhibition via a carboxyl-terminal peptide, βARKct, enhances heart function and can prevent HF development. Mounting evidence supports the idea of a dynamic “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for HF therapy. For instance, GRK2 contains a putative amino-terminal Regulator of G protein Signaling (RGS) domain (βARK-RGS) that directly interacts with Gq and appears to inhibit signaling without altering Gq enzymatic activity. Previously, our lab investigated cardiac-specific transgenic (Tg) expression of a fragment of this RGS domain (βARKnt). This fragment did not alter acute hypertrophy after pressure overload or demonstrate RGS activity in vivo against Gq-mediated signaling. In contrast, βARKnt induced hypertrophy and elevated β-adrenergic receptor (βAR) density without altering agonist-induced contractility or adenylyl cyclase activity, due to a compensatory increase in GRK2 activity. Importantly, though, βAR downregulation in response to chronic agonist administration was attenuated by βARKnt expression, indicating a novel regulation of βAR receptor density. Given these findings we have recently investigated the effect of βARKnt expression during chronic pressure overload post trans-aortic constriction (TAC). Echocardiographic analysis revealed increased posterior wall thickness and left-ventricular mass 4 weeks post-TAC compared to non-transgenic littermate controls (NLC). Importantly, despite enhanced hypertrophy, the progression to HF was inhibited in βARKnt mice 14 weeks post-TAC (%LV Ejection Fraction of 36.1 ± 0.2 in NLC versus 56.6 ± 0.9 in Tg mice). While mechanistic characterization is underway, these data indicate that βARKnt-mediated regulation of βAR density may provide a novel means of cardioprotection during pressure-overload induced HF.
Author Disclosures: S.M. Schumacher: None. E. Gao: None. J. Chuprun: None. W.J. Koch: None.
- © 2015 by American Heart Association, Inc.