Class Ila HDACs in the Heart

Cardiac hypertrophy in response to pathological stimuli has long been viewed as a compensatory mechanism that normalizes wall stress and enhances cardiac performance. However, long-term suppression of cardiac hypertrophy is associated with reduced morbidity and mortality in patients with hypertension, and thus chronic cardiac hypertrophy is now considered maladaptive (Devereux et al. 2004; Gardin and Lauer 2004).

The first connection between HDACs and regulation of pathological cardiac remodeling was provided by the discovery that class IIa HDACs interact with members of the myocyte enhancer factor-2 (MEF2) transcription factor family (McKinsey et al. 2002), which are key regulators on cardiac hypertrophy. The transcriptional activity of MEF2 factors is upregulated in response to pathological stress in the heart (Kolodziejczyk et al. 1999; Lu et al. 2000; Passier et al. 2000; Zhang et al. 2002), and ectopic overexpression of constitutively active forms of MEF2 in mouse heart causes dilated cardiomyopathy (Xu et al. 2006). All class IIa HDACs were found to associate with MEF2 on DNA through a conserved binding domain (Han et al. 2003, 2005), resulting in repression of downstream target genes.

Ectopic overexpression of either HDAC4 (Backs et al. 2006), HDAC5 (Bush et al. 2004; Vega et al. 2004; Zhang et al. 2002) or HDAC9 (Zhang et al. 2002) in cultured rat cardiomyocytes coordinately suppresses MEF2-dependent transcription and agonist-dependent cardiac hypertrophy. In contrast, disruption of the gene encoding HDAC9 in mice leads to superactivation of cardiac MEF2 activity (Zhang et al. 2002), and mouse knockouts for HDAC5 (Chang et al. 2004) or HDAC9 (Zhang et al. 2002) develop exaggerated cardiac hypertrophy in response to pressure overload and spontaneous, pathologic hypertrophy with advancing age. These results support a role for class IIa HDACs as endogenous inhibitors of cardiac hypertrophy.

The ability of class IIa HDACs to block cardiac gene expression appears to be governed not only by direct association with MEF2, but also through indirect interactions with members of the serum response factor (SRF) (Davis et al. 2003; Xing et al. 2006), nuclear factor of activated T cells (NFAT) (Dai et al. 2005) and NK families of transcription factors (Song et al. 2006), all of which have been implicated in the control of pathological cardiac gene expression. In each case, class IIa HDAC binding to the transcription factor is governed by bridging cofactors. HDAC4 is coupled to NFAT by a mammalian relative of DnaJ (Mrj)

(Dai et al. 2005). HDAC5 interacts with SRF via myocardin (Davis et al. 2003; Xing et al. 2006), and CAMTA links HDAC5 to NKX2.5 (Song et al. 2006).

Although knocking out class IIa HDACs in the heart appears to be generally detrimental, in some cases class IIa HDAC deletion is beneficial. Removal of HDAC5 or HDAC9 in female mice results in protection from postmyocardial infarction (MI) remodeling due to enhanced estrogen receptor-mediated transcription of proangiogenic genes in the heart. Interestingly, however, male knockout mice succumb to MI at a higher frequency than male, wild-type littermates (van et al. 2010).

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