Cellular Biology 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 ␤-adrenergic receptor (␤-AR) agonist isoproterenol (ISO), may regulate HDAC5 nuclear localization in adult cardiac myocytes. 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 ␤ 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 ␤ 1-AR antagonists in heart failure. Key Words: cardiac hypertrophy Ⅲ histone deacetylases Ⅲ myocyte enhancer factor 2 Ⅲ protein kinases Ⅲ signal transduction A substantial body of evidence indicates that the activity of myocyte enhancer factor 2 (MEF2) transcription factors is a critical driver of the pathological cardiac hyper-trophy and remodeling processes that culminate in heart failure, in both acquired 1 and genetic 2 forms of the disease. An extensive series of studies in recent years, particularly in the Olson laboratory, have revealed that class II histone deacetylase (HDAC) isoforms, such as HDAC4 and HDAC5, act as signal-responsive repressors of nuclear MEF2 activity in cardiac myocytes and that their spatial regulation provides a key mechanism for the neurohormonal control of such activity. 3,4 The compelling scheme that has emerged is that HDAC4 and HDAC5 are direct substrates for serine/threo-nine protein kinases of the Ca 2ϩ /calmodulin-dependent ki-nase (CaMK) superfamily, such as CaMKII 5 and protein kinase D (PKD), 6 and that the phosphorylation by such kinases of conserved residues that flank nuclear localization signal domains in HDAC4/5 leads to their exclusion from the nucleus and consequent derepression of MEF2 activity. 7–12 Recent studies suggest that protein kinase A (PKA) may also regulate MEF2 activity through HDAC-mediated mechanisms , but in an opposing manner, by promoting HDAC5 nuclear retention 13 or HDAC4 proteolytic cleavage. 14 Finally, there is emerging evidence that HDAC nuclear localization may be regulated additionally by a novel, phosphorylation-independent mechanism, through redox-dependent modification of reactive cysteine residues in HDAC4. 15 How these different …