HDAC Inhibition in the Heart

Abstract

lterations in the transcriptional profile of cells govern downstream events fundamental to both physiology and pathology. Central in this control of transcription are changes in chromatin structure elicited by post-translational modifications of histone proteins. The protein machinery that act to add, remove, or detect these modifications are known colloquially as writers, erasers, and readers of histone modifications. 2 There is great interest in the clinical application of small molecules that alter the activity of these proteins in the hope of fostering clinical benefit. Small molecule inhibitors of a class of "erasers" known as histone deacetylases (HDACs) have made their way to the clinic. s the name implies, HDAC proteins remove acetyl groups from histone protein tails, but they can also target nonhistone proteins. HDACs fall into 4 different classes (I, II, III, and IV). Class I, II, and IV share a conserved zinc-dependent functional domain and most small molecule inhibitors in use target that domain. number of HDAC inhibitors (HDACis) have been approved by the US Food and Drug Administration for the treatment of various cancers, with >60 clinical trials reported as currently active on clinicaltrials.gov. The list of approved drugs includes the pan-HDACis vorinostat, panobinostat, and belinostat, which inhibit class I, II, and IV HDACs, and the more specific class I HDACi romidepsin. Treatment with a pan-HDACi resulted in a blunting of the hypertrophic response and a slowing of progression to failure. 5 HDACi was also capable of promoting regression of established hypertrophy. 7 These opposing data suggest that class I HDAC activity may dominate class II-dependent events in the response to hypertrophic stress.

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