AbstractG protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 “interactome” that underlies a great diversity in its functional roles. Several such 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 heart failure therapy. While elevated cardiac levels and activity of GRK2 contribute to adverse heart remodeling and contractile dysfunction, inhibition of GRK2 via overexpression of a carboxyl-terminal peptide, βARKct, or its amino-terminal domain Regulator of G protein Signaling (RGS) homology domain (βARKrgs) can enhance cardiac function and can prevent heart failure development via Gβγ or Gαq sequestration, respectively. Previously, our lab investigated cardiac-specific transgenic expression of a fragment of this RGS domain (βARKnt) (residues 50-145). In contrast to βARKrgs this fragment did not alter acute hypertrophy after pressure overload or demonstrate RGS activity in vivo against Gq-mediated signaling. Herein, we subjected these transgenic mice to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, βARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, βARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. These data support the idea that the βARKnt peptide embodies a distinct functional interaction and novel means of cardioprotection during pressure-overload induced heart failure.
Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure