LAUSR

Histone deacetylases (HDACs) are epigenetic regulators with imporConsistent with the observed reductions in apoptotic, oxidative stress tant roles in numerous cellular processes. The HDAC superfamily is divided into four classes based on function and sequence similarity. The zinc-dependent class I, II and IV HDACs have been implicated in a range of processes relevant to cardiovascular diseases, including cardiac hypertrophy, fibrosis, calcium handling and inflammation [1]. Over the past decade, several groups have demonstrated that HDAC inhibitors (HDACi), such as the pan-HDACi suberoylanilide hydroxamic acid (SAHA), can reduce infarct size and attenuate pathological cardiac remodelling in rodent and rabbit models of myocardial infarction (MI) and ischemia/reperfusion injury (see Table 1 in [2] for summary). Current research focuses on elucidating the mechanisms by which HDACs contribute to cardiac remodelling and dysfunction, with the hope that more targeted approaches or the development of isoform-selective HDACi may provide a more favourable therapeutic index than panHDACi for the treatment of cardiovascular and metabolic diseases. In this article of EBioMedicine, Tian and colleagues [3] identify one of the mechanisms by which valproic acid (VPA), a branched short-chain fatty acid that weakly inhibits both class I and class IIa HDACs [4], may provide protection in a setting ofmyocardial infarction (MI). VPA is routinely used in the treatment of epilepsy and bipolar disorder [5], and daily administration of VPA has previously been shown to attenuate pathological cardiac remodelling in an experimental model of MI [6]. In the current study, rats were subjected to 60 min of myocardial ischemia induced by occlusion of the left descending coronary artery (LAD) and dissected 24 h after the onset of reperfusion. VPA (250 mg/kg) was administered intraperitoneally upon LAD occlusion or at the time of reperfusion, as well as 12 h post-LAD ligation. VPA reduced infarct size, improved left ventricular ejection fraction, and attenuatedmarkers of apoptosis, oxidative stress and myocardial injury. Improved systolic function and smaller infarct size were also observed in a group of animals that received VPA twice daily for 4 weeks post-MI. To identify possible mechanisms by which VPA provided cardioprotection in thismodel, RNA-Seqwas performed on left ventricular tissue from shamandMI-operated rats, with andwithout VPA treatment.