Work is presently underway to unveil mechanisms whereby SAHA

Work is presently underway to unveil mechanisms whereby SAHA-dependent restoration of cardiomyocyte autophagic flux is protective. Another interesting question pertains to mechanisms whereby class I and class II HDAC inhibitors induce autophagy. It has been demonstrated that TSA reduces transverse aortic banding-induced cardiac hypertrophy [37]. Recent data demonstrate that inhibition of class I HDACs with apicidin induces the Boc-D-Asp(OtBu)-OH.DCHA of tuberous sclerosis complex 2 (TSC2), an mTOR inhibitor, which inhibits mTOR-mediated cardiac hypertrophy [38]. Since mTOR is a strong modulator of autophagy [39], inhibition of class I HDACs may induce autophagy at least partially through this pathway. Interestingly, β-hydroxybutyrate (β-OHB) at physiological levels functions as an endogenous HDAC inhibitor [40] and induces autophagy in neurons [41]. In the kidney, β-OHB promotes acetylation of the promoters of the genes coding for FoxO3a and MT2 transcription factors, which upregulates their expression to activate the downstream targets SOD2 and catalase [40]. These, in turn, elicit reductions in ROS and protect the kidney from I/R injury [40]. Delivery of exogenous β-OHB or increasing β-OHB by fasting immediately prior to I/R, reduces cardiac infarct size in rats [42,43]. These findings suggest cardioprotective effects of β-OHB, possibly via activation of autophagy, and point to possible links among metabolism, HDAC biology, and cardiomyocyte I/R tolerance. There are few data on the effects of genetic manipulation of HDACs during cardiac I/R. First, we do not know which HDACs are the functionally relevant targets of HDAC inhibition. Second, HDACs are vital for multiple other cellular functions; most constitutive knockouts and even tissue-specific knockouts manifest baseline phenotypes, including cardiac hypertrophy [44]. Last but not least, it is challenging to mimic the small molecule-dependent, reversible suppression of HDACs with a genetic model. Experimental up-regulation of HDAC4 activity has provided some rationale for genetic manipulation of HDACs in cardiac I/R injury [24], but our understanding of HDAC function during cardiac I/R remains incomplete.
FDA-approved, pharmaceutical grade, small molecule HDAC inhibitors that could be used in clinical trials As mentioned above, it is challenging to design a clinical trial to evaluate a strategy of myocardial protection during reperfusion injury; indeed, specific requirements have been laid out [5] [9]. SAHA has satisfied most of them: tested at the time of reperfusion; confirmed in large-animal models; safe and available pharmaceutical grade agent; efficacy verified in multiple laboratories; robustness of response; preclinical studies conducted in a randomized, blinded fashion [26]. Two caveats that remain are that SAHA has never been tested in animals with comorbidities, and long-term effects beyond infarct size have not been evaluated. However, recent data in diabetic rats demonstrating that pretreatment with TSA significantly reduces infarct size offer hope that SAHA may have efficacy in a myocardial infarct population with diabetes [21]. Furthermore, it has been shown that long-term exposure to low-dose TSA or SAHA reduces post-infarct adverse remodeling, suggesting that SAHA's cardioprotective effects may be enduring and translate into improved clinical outcomes [28,31]. There are several reported side effects of HDAC inhibitors in cancer treatment, including gastrointestinal upset, fatigue, thrombocytopenia, anemia and bone marrow toxicity, and reversible cardiac arrhythmia (FK-228, cyclic depsipeptide) [27]. It is worth noting, however, that SAHA manifests no signs of cardiotoxicity [27]. With respect to cardiac I/R, it seems unlikely that a single dose administered at the time of cardiac reperfusion during MI will elicit untoward effects outside the heart. Furthermore, as there are multiple FDA-approved HDAC inhibitors available or in the pipeline for cancer therapy [18], we may be able to refine our therapeutic approaches for optimal efficacy and minimal off-target effects.