Rationale: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear. Objective: Recently, we suggested that casein kinase 2α1–dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5. Methods and Results: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress–induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced. Conclusions: Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.

Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.

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Cardiac hypertrophy is an increase in the individual cellular volume of the heart and is an adaptive response to exogenous stresses. The increase in cellular volume is associated with reactivation of the fetal gene program, which is finely regulated by diverse cardiac transcription factors.1 Specifically, GATA4, GATA6, myocyte enhancer factor 2C, nuclear factor of activated T cells, NK2 homeobox 5, and serum response factor have been shown to be involved in the development of cardiac hypertrophy.1 GATA4 and GATA6 are heart-specific transcription factors that regulate pathological cardiac hypertrophy in association with atrial natriuretic factor (ANF) expression.2,3 Transgenic mice that overexpress GATA4 in the heart show cardiac hypertrophy, 4 and GATA4 activity is regulated by physical interaction with other transcription factors, such as serum response factor, NK2 homeobox 5, and myocyte enhancer factor 2.5-7 GATA6 also induces pathological cardiac hypertrophy, which was demonstrated by recent studies of cardiac-specific overexpression of GATA6 in mice. 3In addition to effects as transcription factors, some of these factors also act as nuclear receptors that provide signal-mediated responsiveness to endogenous or exogenous ligands. For example, peroxisome proliferator-activated receptor-α or steroid receptors respond to a ligand and then mediate diverse cellular events as well as metabolic regulation.8,9 Not surprisingly, these nuclear receptors also play important roles in various organs, and therapeutic applications of their modulators are growing. The nuclear receptors are classified depending on their structural similarities. Interestingly, 1 group of nuclear receptors is termed the orphan nuclear receptors. In contrast with the other nuclear receptors that have endogenous ligands

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