title: Determining the absolute requirement of G protein-coupled receptor kinase 5 for pathological cardiac hypertrophy: short communication.
abstract: BACKGROUND
  Heart failure (HF) is often the end phase of maladaptive cardiac hypertrophy. A contributing factor is activation of a hypertrophic gene expression program controlled by decreased class II histone deacetylase (HDAC) transcriptional repression via HDAC phosphorylation. Cardiac-specific overexpression of G proteinen-coupled receptor kinase-5 (GRK5) has previously been shown to possess nuclear activity as a HDAC5 kinase, promoting an intolerance to in vivo ventricular pressure overload; however, its endogenous requirement in adaptive and maladaptive hypertrophy remains unknown.
  
  
  OBJECTIVE
  We used mouse models with global or cardiomyocyte-specific GRK5 gene deletion to determine the absolute requirement of endogenous GRK5 for cardiac hypertrophy and HF development after chronic hypertrophic stimuli.
  
  
  RESULTS
  Mice with global deletion of GRK5 were subjected to transverse aortic constriction. At 12 weeks, these mice showed attenuated hypertrophy, remodeling, and hypertrophic gene transcription along with preserved cardiac function. Global GRK5 deletion also diminished hypertrophy and related gene expression due to chronic phenylephrine infusion. We then generated mice with conditional, cardiac-specific deletion of GRK5 that also demonstrated similar protection from pathological cardiac hypertrophy and HF after transverse aortic constriction.
  
  
  CONCLUSIONS
  These results define myocyte GRK5 as a critical regulator of pathological cardiac growth after ventricular pressure overload, supporting its role as an endogenous (patho)-physiological HDAC kinase. Further, these results define GRK5 as a potential therapeutic target to limit HF development after hypertrophic stress.
authors.affiliation: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Xiying
authors.initials: X
authors.lastname: Shang
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D010656:Phenylephrine; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse