title: Neurohormonal regulation of cardiac histone deacetylase 5 nuclear localization by phosphorylation-dependent and phosphorylation-independent mechanisms.
abstract: BACKGROUND
  Myocyte enhancer factor 2 (MEF2) transcription factors drive the genetic reprogramming that precipitates pathological cardiac hypertrophy and remodeling. Class II histone deacetylase (HDAC) isoforms, such as HDAC5, act as signal-responsive repressors of MEF2 activity in cardiac myocytes and their nuclear export provides a key mechanism for the neurohormonal induction of such activity.
  
  
  OBJECTIVE
  To delineate the mechanism(s) through which 2 clinically relevant neurohormonal stimuli, endothelin-1 (ET1) and the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO), may regulate HDAC5 nuclear localization in adult cardiac myocytes.
  
  
  RESULTS
  ET1 induced HDAC5 phosphorylation and nuclear export in ventricular myocytes from the adult rat heart. Use of a novel, highly selective protein kinase D (PKD) inhibitor and a nonphosphorylatable HDAC5 mutant revealed that PKD-mediated phosphorylation was necessary for ET1-induced HDAC5 nuclear export. In contrast, ISO reduced HDAC5 phosphorylation in the presence or absence of ET1 but still induced HDAC5 nuclear export. ISO-induced HDAC5 nuclear export occurred through a β(1)-AR-mediated oxidative process that was independent of PKD, protein kinase A, and Ca(2+)/calmodulin-dependent kinase II activities. Although ET1 and ISO shared a similar ability to induce HDAC5 nuclear export, albeit through distinct phosphorylation-dependent versus phosphorylation-independent mechanisms, ISO induced a significantly greater increase in MEF2 activity.
  
  
  CONCLUSIONS
  PKD-mediated HDAC5 phosphorylation and nuclear export are unlikely to be of major importance in regulating MEF2-driven cardiac remodeling in the presence of sympathetic activity with intact β(1)-AR signaling, which would not only counteract HDAC5 phosphorylation but also induce HDAC5 nuclear export through a novel phosphorylation-independent, oxidation-mediated mechanism. Inhibition of this mechanism may contribute to the therapeutic efficacy of β(1)-AR antagonists in heart failure.
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Haworth
authors.forename: Konstantina
authors.initials: K
authors.lastname: Stathopoulou
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Candasamy
authors.forename: Metin
authors.initials: M
authors.lastname: Avkiran
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D006655:Histone Deacetylases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats
chemical_list: D018377:Neurotransmitter Agents; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases