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

RATIONALE 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.