Abstract | RATIONALE: 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.
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Authors | Robert S Haworth, Konstantina Stathopoulou, Alexandra J Candasamy, Metin Avkiran |
Journal | Circulation research
(Circ Res)
Vol. 110
Issue 12
Pg. 1585-95
(Jun 08 2012)
ISSN: 1524-4571 [Electronic] United States |
PMID | 22581927
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Neurotransmitter Agents
- Hdac5 protein, rat
- Histone Deacetylases
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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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