Abstract 574: An Amino-Terminal Peptide of GRK5 Prevents Pathological Cardiac Hypertrophy in Response to Pharmacological and Surgical Stress

Abstract

Introduction: The pathogenesis and progression of heart failure (HF) encompasses maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. A gene expression maladaptation in HF is an increase in expression of G protein-coupled receptor kinase (GRK5). Recently, non-canonical roles for GRK5 have been uncovered that are crucial for the development of maladaptive hypertrophy and these are due to its nuclear translocation. We have shown that nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that can bind calmodulin. Hypothesis: We hypothesize that expression of a peptide encoding the NT of GRK5 that includes this calmodulin binding domain will act as a calmodulin inhibitor preventing the nuclear accumulation of GRK5 and inhibit its non-canonical pathological activities. Methods: To further study this, neonatal rat ventricular cardiomyocytes overexpressing GRK5-NT or a negative control virus were treated with 50μM phenylephrine (PE) or vehicle for 48 hours to induce a hypertrophic response. Cell areas and transcript levels of fetal genes were measured after treatment. Novel transgenic GRK5-NT and non-transgenic littermate control (NLC) mice were characterized before and 4 weeks after transverse aortic constriction (TAC) or sham surgery. Echocardiography, myocyte cross-sectional area, and heart weight to tibia length metrics were used to evaluate TAC response. Results: In vitro, expression of the GRK5-NT peptide abrogated the hypertrophic effects of PE, both in terms of fetal gene re-activation and myocyte size. In vivo, transgenic GRK5-NT mice did not demonstrate any hypertrophy after 4 weeks of TAC and cardiac dysfunction seen in NLC mice at this time point was absent in GRK5-NT mice. Further, GRK5-NT TAC mice showed no increase in cell surface area compared to their respective sham controls post-TAC. Conclusion: In this study, we show that the GRK5-NT peptide prevents the pathological response to pharmacological and surgical models of cardiac hypertrophy. Further studies in vivo will reveal whether GRK5-NT can preserve function in the long-term, and further in vitro characterization will reveal whether the mechanism is GRK5-dependent.