title: GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity.
abstract: BACKGROUND
  G protein-coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failing human myocardium. Although the canonical role of GRKs is to desensitize G protein-coupled receptors via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert G protein-coupled receptor-independent effects that promote maladaptive cardiac hypertrophy and heart failure.
  
  
  OBJECTIVE
  To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy.
  
  
  RESULTS
  In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of the nuclear factor of activated T cells (NFAT) because GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimulation, including transverse aortic constriction and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after transverse aortic constriction. Furthermore, the loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to heart failure seen after transverse aortic constriction. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5's ability to bind DNA directly without a phosphorylation event.
  
  
  CONCLUSIONS
  GRK5, acting in a kinase independent manner, is a facilitator of NFAT activity and part of a DNA-binding complex responsible for pathological hypertrophic gene transcription.
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Hullmann
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Grisanti
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: From the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.E.H., J.I.G.); and Center for Translational Medicine (J.E.H., L.A.G., E.G. J.I.G., J.K.C., D.G.T., W.J.K.) and Cardiovascular Research Center (C.A.M., S.R.H.), Temple University School of Medicine, Philadelphia, PA. Walter.Koch@temple.edu.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D001665:Binding Sites; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse
keywords: G protein–coupled receptor kinase; heart failure; nuclear factor of activated T cells