title: Differential Role of G Protein-Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy.
abstract: BACKGROUND
  G protein-coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein-coupled receptor signaling, recent data has uncovered noncanonical activity of GRK5 within nuclei that plays a key role in pathological hypertrophy. Targeted cardiac elevation of GRK5 in mice leads to exaggerated hypertrophy and early heart failure after transverse aortic constriction (TAC) because of GRK5 nuclear accumulation.
  
  
  OBJECTIVE
  In this study, we investigated the role of GRK5 in physiological, swimming-induced hypertrophy (SIH).
  
  
  RESULTS
  Cardiac-specific GRK5 transgenic mice and nontransgenic littermate control mice were subjected to a 21-day high-intensity swim protocol (or no swim sham controls). SIH and specific molecular and genetic indices of physiological hypertrophy were assessed, including nuclear localization of GRK5, and compared with TAC. Unlike after TAC, swim-trained transgenic GRK5 and nontransgenic littermate control mice exhibited similar increases in cardiac growth. Mechanistically, SIH did not lead to GRK5 nuclear accumulation, which was confirmed in vitro as insulin-like growth factor-1, a known mediator of physiological hypertrophy, was unable to induce GRK5 nuclear translocation in myocytes. We found specific patterns of altered gene expression between TAC and SIH with GRK5 overexpression. Further, SIH in post-TAC transgenic GRK5 mice was able to preserve cardiac function.
  
  
  CONCLUSIONS
  These data suggest that although nuclear-localized GRK5 is a pathological mediator after stress, this noncanonical nuclear activity of GRK5 is not induced during physiological hypertrophy.
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Traynham
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: Vouga
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Woodall
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hullmann
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibetti
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA (C.J.T., A.C., A.G.V., B.P.W., J.H., J.I., J.I.G., J.K.C., E.G., W.J.K.); and Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA (Y.Z.). Walter.Koch@temple.edu.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse
keywords: G protein–coupled receptor; exercise; heart failure; hypertrophy; myocardium