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.