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Neurohormonal regulation of cardiac histone deacetylase 5 nuclear localization by phosphorylation-dependent and phosphorylation-independent mechanisms.

AbstractRATIONALE:
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.
METHODS AND 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.
AuthorsRobert S Haworth, Konstantina Stathopoulou, Alexandra J Candasamy, Metin Avkiran
JournalCirculation research (Circ Res) Vol. 110 Issue 12 Pg. 1585-95 (Jun 08 2012) ISSN: 1524-4571 [Electronic] United States
PMID22581927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Neurotransmitter Agents
  • Hdac5 protein, rat
  • Histone Deacetylases
Topics
  • Active Transport, Cell Nucleus (physiology)
  • Animals
  • Cell Nucleus (enzymology, metabolism)
  • Cells, Cultured
  • Histone Deacetylases (metabolism)
  • Myocytes, Cardiac (enzymology, metabolism)
  • Neurotransmitter Agents (physiology)
  • Phosphorylation (physiology)
  • Rats

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