Efficacy of HDAC Inhibitors in Preclinical Models of Heart Failure

Since class IIa HDACs function as suppressors of cardiac hypertrophy, HDAC inhibitors were initially expected to promote hypertrophy. However, experiments with cultured cardiac myocytes revealed that HDAC inhibitors effectively suppress myocyte hypertrophy (Antos et al. 2003). There are at least two explanations for these seemingly paradoxical findings. First, as mentioned above, the class Ila HDAC enzymatic assay revealed that these HDACs are relatively insensitive to standard HDAC inhibitors, including those used in the initial hypertrophy studies (Bradner et al. 2010). Second, it was determined that class Ila HDACs do not require catalytic activity to suppress hypertrophic signaling (Zhang et al. 2002).

Follow-up in vivo studies further validated the protective activity of HDAC inhibitors in the heart (Fig. 3). Treatment with the hydroxamic acid, pan-HDAC

Class I HDAC1 H0AC2 HDAC3 HDAC8

ClaaaJla

HDAC4 HDAC5 HDAC7 HDAC9

Class lib HDAC6 HDAC10

Class IV HDAC 11

Fig. 3 In vitro and in vivo activity of HDAC inhibitors used in heart failure models. The indicated compounds have been tested in models of heart failure. The values represent activities of compounds against recombinant HDAC isoforms. Values (nM) for trichostatin A (TSA), scriptaid and SAHA are dissociation constants (Ki) (Bradner et al. 2010), while those for apicidin-derivative (Api-D) (Gallo et al. 2008) and valproic acid (VPA) (Gurvich et al. 2004; Khan et al. 2008) are half maximal inhibitory concentrations (IC50). - no activity; N/A not available. The rodent heart failure models in which the compounds have shown efficacy are indicated. TAC transverse aortic constriction; MI myocardial infarction; Angll angiotensin II; ISO isoproterenol; Hop-Tg homeodomain only protein transgenic; DOCA deoxycorticosterone acetate; SHR spontaneously hypertensive rat

Fig. 3 In vitro and in vivo activity of HDAC inhibitors used in heart failure models. The indicated compounds have been tested in models of heart failure. The values represent activities of compounds against recombinant HDAC isoforms. Values (nM) for trichostatin A (TSA), scriptaid and SAHA are dissociation constants (Ki) (Bradner et al. 2010), while those for apicidin-derivative (Api-D) (Gallo et al. 2008) and valproic acid (VPA) (Gurvich et al. 2004; Khan et al. 2008) are half maximal inhibitory concentrations (IC50). - no activity; N/A not available. The rodent heart failure models in which the compounds have shown efficacy are indicated. TAC transverse aortic constriction; MI myocardial infarction; Angll angiotensin II; ISO isoproterenol; Hop-Tg homeodomain only protein transgenic; DOCA deoxycorticosterone acetate; SHR spontaneously hypertensive rat inhibitor, trichostatin A (TSA) or the short chain fatty acid, valproic acid, for 2 weeks blocked the development of cardiac hypertrophy in transgenic mice that overexpress an HDAC2-dependent SRF inhibitor, Hop (Kook et al. 2003). Similar 2-week regimens of pan-HDAC inhibitor treatment also effectively suppressed cardiac hypertrophy induced by continuous infusion of isoproterenol (Kook et al. 2003) or angiotensin II (Kee et al. 2006), as well as pressure-overload imposed by aortic constriction (Kee et al. 2006). Importantly, TSA treatment was also shown to regress established cardiac hypertrophy in mice subjected to aortic constriction (Kee et al. 2006), suggesting potential therapeutic benefit of HDAC inhibitors for pre-established heart failure. Of note, data obtained with valproic acid should be interpreted cautiously because this compound is a weak HDAC inhibitor (Gurvich et al. 2004; Khan et al. 2008) that is associated with a plethora of other pharmacological activities, including regulation of glycogen synthase kinase-3p, mitogen-activated protein kinases and ion channels (Terbach and Williams 2009).

Subsequent studies confirmed that 3 weeks of treatment with TSA and another pan-HDAC inhibitor, scriptaid, blunted cardiac hypertrophy in a pressure-overload mouse model, reducing cardiomyocyte cross-sectional area and significantly improving ventricular performance (Kong et al. 2006). The reduction in cardiac hypertrophy and functional improvements were maintained at 9 weeks, and TSA appeared to be well tolerated, because chronic administration over the course of the investigation did not adversely impact survival. Pan-HDAC inhibitors have also been shown to reduce maladaptive ventricular remodeling and improve cardiac performance in rodent models of myocardial infarction (Granger et al. 2008; Lee et al. 2007; Zhao et al. 2007), and in the setting of chronic hypertension in rats (Cardinale et al. 2010; Iyer et al. 2010). Valproic acid was recently shown to block right ventricular hypertrophy in response to pulmonary artery banding and monocrotaline-induced lung injury (Cho et al. 2010). However, as mentioned above, since valproic acid has many pharmacological activities, it is difficult to know whether the efficacy observed in these models was a consequence of HDAC inhibition.

It will be essential to determine the HDAC isoform(s) that promote pathological growth of the heart. As described above, although genetic studies suggested a role for HDAC2 in the process (Kee et al. 2008; Trivedi et al. 2007), the findings remain controversial (Montgomery et al. 2007). More definitive answers will likely come from the use of small molecule inhibitors of select HDAC isoforms. SK-7041, a hydroxamic acid HDAC inhibitor that is reportedly specific for class I HDACs, was shown to block hypertrophy in mice in response to aortic constriction and angiotensin II (Kee et al. 2006). However, independent evaluation of SK-7041 in vitro revealed that the compound is a pan-HDAC inhibitor (E.W. Bush and T.A. McKinsey, unpublished observations). More recently, an apicidin derivative, which is predominantly selective for class I HDACs 1, 2 and 3, was shown to effectively suppress hypertrophy and improve cardiac performance in the setting of pressure overload (Gallo et al. 2008). However, this compound appeared to exhibit activity, albeit modest, against HDAC6 in vitro. An essential next step is to extend these findings by testing benzamide HDAC inhibitors that inhibit class I HDACs but are devoid of HDAC6 inhibitory activity, and newer generations of HDAC1/

2-, HDAC3-, HDAC6- and HDAC8-selective compounds in animal models of pathological cardiac remodeling.

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