Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart

Metabolomics — A wide-open door to personalized treatment in chronic heart failure?

“…Although, in the face of multitude of information that -omics technologies may offer for scientists, it is a huge challenge to correctly interpret the biochemical and pathophysiological roles of enzymes, their metabolites and metabolic networks. The results of experimental studies on possible targets for metabolic interventions seem to be promising [92][93]. Therefore also a number of therapies targeting cardiac metabolism is still growing, although solely some of them are already available for clinical use.…”

The changing landscape of cardiac metabolism

“…Also, metabolic signals can participate in gene regulation by modifying the expression of transcription factors such as myocyte enhancer factor 2C in failing hearts [42]. Now, with their contribution, Matsuhashi et al have not only provided further evidence supporting this notion, but also probed the possibility of using pharmacological interventions to modify the transcriptome through epigenetic changes in order to prevent heart disease development/progression in vivo [8].…”

“…The study of epigenetics, or, as Waddington defined it, the "interactions of genes with their environment which bring the phenotype into being" [5,6] is providing additional insight into the mechanisms underlying this memory. The substrates required for all four forms of epigenetic changes, namely DNA methylation, covalent histone modifications, ATP-dependent chromatin remodeling and non-coding RNA-mediated pathways [7], are either derived from, or connected to, intermediary metabolism of energy providing substrates.Building on this principle, Matsuhashi et al have shown the equally intriguing possibility of intervening in this memory using drugs that change the epigenome and eventually transcription, through metabolic modulation [8]. In other words, a drug which changes the activity of an enzyme, acts through the metabolite produced by the enzymatic reaction to leave a lasting, epigenomic, imprint.…”

“…Building on this principle, Matsuhashi et al have shown the equally intriguing possibility of intervening in this memory using drugs that change the epigenome and eventually transcription, through metabolic modulation [8]. In other words, a drug which changes the activity of an enzyme, acts through the metabolite produced by the enzymatic reaction to leave a lasting, epigenomic, imprint.…”

“…This agent is a potent pharmacologic activator of the pyruvate dehydrogenase complex (PDHC) [16], the rate limiting enzyme of aerobic oxidation of glucose, pyruvate and lactate [17]. PDHC activation by DCA occurs by inhibition of its inhibitor (pyruvate dehydrogenase kinases) [8,17]. The use of DCA has been proposed as a therapeutic agent for diabetes mellitus, hyperlipidemia [18] and lactic acidosis [16,19,20].…”