The Nonepigenetic Role for Small Molecule Histone Deacetylase Inhibitors in the Regulation of Cardiac Function

Eight million US adults are projected to suffer from heart failure (HF) by 2030. Of concern, 5-year mortality rates following HF diagnosis approximate 40%. Small molecule histone deacetylase (HDAC) inhibitors have demonstrated efficacy for the treatment and reversal of HF. Historically, HDACs were studied as regulators of nucleosomal histones, in which lysine deacetylation on histone tails changed DNA-histone protein electrostatic interactions, leading to chromatin condensation and changes in gene expression. However, recent proteomics studies have demonstrated that approximately 4500 proteins can be acetylated in various tissues; the function of most of these remains unknown. This Review will focus on the nonepigenetic role for lysine acetylation in the heart, with a focus on nonepigenetic actions for HDAC inhibitors on cardiac function.