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

TY - JOUR

T1 - Neurohormonal regulation of cardiac histone deacetylase 5 nuclear localization by phosphorylation-dependent and phosphorylation-independent mechanisms

AU - Haworth, Robert S

AU - Stathopoulou, Konstantina

AU - Candasamy, Alexandra J

AU - Avkiran, Metin

PY - 2012/6/8

Y1 - 2012/6/8

N2 - 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 beta-adrenergic receptor (beta-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 beta(1)-AR-mediated oxidative process that was independent of PKD, protein kinase A, and Ca2+/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 beta(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 beta(1)-AR antagonists in heart failure. (Circ Res. 2012;110:1585-1595.)

AB - 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 beta-adrenergic receptor (beta-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 beta(1)-AR-mediated oxidative process that was independent of PKD, protein kinase A, and Ca2+/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 beta(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 beta(1)-AR antagonists in heart failure. (Circ Res. 2012;110:1585-1595.)

KW - INHIBITORS

KW - cardiac hypertrophy

KW - TROPONIN-I

KW - signal transduction

KW - HEART-FAILURE

KW - MYOCARDIUM

KW - ACTIVATION

KW - myocyte enhancer factor 2

KW - PROTEIN-KINASE-D

KW - VENTRICULAR MYOCYTES

KW - RECEPTOR

KW - histone deacetylases

KW - TRANSCRIPTION

KW - protein kinases

KW - HYPERTROPHY

U2 - 10.1161/CIRCRESAHA.111.263665

DO - 10.1161/CIRCRESAHA.111.263665

M3 - Article

C2 - 22581927

SN - 0009-7330

VL - 110

SP - 1585

EP - 1595

JO - Circulation Research

JF - Circulation Research

IS - 12

ER -