Class Iii Hdacs in the Heart

Class III HDACs (sirtuins), which are NAD+ dependent, appear to serve protective functions in the heart. SIRT1 overexpression enhances the survival of cultured neonatal rat cardiomyocytes under conditions of serum starvation (Alcendor et al. 2004). In vivo, transgenic overexpression of moderate levels of SIRT1 in mouse heart protects against cardiac apoptosis and hypertrophy in response to aging and oxidative stress (Alcendor et al. 2007). In contrast, suppression of endogenous SIRT1 activity with a small molecule inhibitor of class III HDACs results in exaggerated apoptosis (Alcendor et al. 2004).

The mechanisms whereby class III HDAC activity protects cardiomyocytes from apoptosis appear to involve repression of p53 and increased expression of antioxidants, such as catalase, via induction of the FoxO transcription factor. In addition, class III HDACs target a prohypertrophic histone variant, H2A.z, for degradation by the ubiquitin-proteasome pathway (Chen et al. 2006). SIRT1 has been shown to associate with MEF2 via HDAC4 and deacetylate MEF2, which would be predicted to result in repression of downstream target genes that promote cardiac hypertrophy (Zhao et al. 2005).

SIRT3 and SIRT7 have also been implicated as cardioprotective factors. SIRT3 overexpression protects cultured cardiac myocytes from apoptosis by promoting deacetylation of Ku70 (Sundaresan et al. 2008). Hypo-acetylated Ku70 physically associates with Bax and neutralizes the proapoptotic function of this protein.

The most compelling evidence of a cardioprotective role for class III HDACs came from studies of SIRT7 deficient mice. SIRT7 knockout mice develop cardiac hypertrophy with severe interstitial fibrosis, which is associated with massive apoptosis of cardiac myocytes (Vakhrusheva et al. 2008). Similar to SIRT1, SIRT7 appears to inhibit apoptosis by deacetylating and thus inhibiting the activity of p53.

Resveratrol is a polyphenol found in the skin of red grapes; it is capable of stimulating class III HDAC activity. Interestingly, resveratrol has been shown to inhibit cardiac hypertrophy (Chan et al. 2008; Cheng et al. 2004; Juric et al. 2007; Liu et al. 2005; Biala et al. 2010; Sulaiman et al. 2010), suggesting an approach to heart failure therapy involving class III HDAC activation. However, it should be noted that many HDAC-independent functions of resveratrol have been described (Pirola and Frojdo 2008), and the antihypertrophic action of the compound was recently attributed to activation of AMP-activated Protein Kinase (AMPK) (Chan et al. 2008).

6 HDAC Inhibitors

Dysregulation of HDACs is associated with a variety of pathophysiological processes, including cancer, neurodegeneration and inflammation. As such, there is focus in the pharmaceutical industry and in academic labs on the development of novel small molecule inhibitors of HDACs, particularly since the first HDAC inhibitor reached the market in 2006 with the FDA approval of SAHA/vorinostat (Zolinza) for the treatment of cutaneous T cell lymphoma (Marks and Breslow 2007).

Most HDAC inhibitors possess a stereotypical three-part structure consisting of a zinc-binding "warhead" group that docks in the active site, a linker and a surface recognition domain that interacts with residues near the entrance to the active site. This general HDAC inhibitor pharmacophore is represented in at least four chemical classes: hydroxamic acids, short chain fatty acids, benzamides and cyclic peptides. Relative potencies and selectivity profiles differ between and within these classes (Bradner et al. 2010). The strong zinc-chelating properties of the hydroxamic acid warhead produce potent (low nanomolar) pan-HDAC inhibitors. In contrast, the short chain fatty acids are weak (millimolar) HDAC inhibitors, with perhaps modest selectivity towards class I HDACs. Benzamide HDAC inhibitors are generally highly selective for HDACs 1, 2 and 3, as are the cyclic peptides.

Compounds containing aryl substitutions on the benzamide warhead have recently been found to be highly selective for HDAC1 and HDAC2 over all other HDACs (Methot et al. 2008; Moradei et al. 2007; Wilson et al. 2008; Witter et al. 2008). Conversely, other benzamide scaffolds appear to be selective for HDAC3 (Chen et al. 2009). Facilitated by the solution of the human HDAC8 crystal structure (Vannini et al. 2004), selective hydroxamic acid inhibitors of this distinct class I HDAC subfamily member have recently emerged (Balasubramanian et al. 2008; Krennhrubec et al. 2007). Finally, the first known HDAC6/class IIb-selective inhibitor, tubacin, was described in 2003 (Haggarty et al. 2003). More recent compounds, such as tubastatin A (Butler et al. 2010), exhibit greater selectivity for HDAC6 than tubacin.

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