Gilham D, et al. - Since apabetalone (an inhibitor of bromodomain and extraterminal [BET] proteins) has been reported to reduce the incidence of major adverse cardiac events (MACE) in patients with cardiovascular disease and reduced circulating factors that promote vascular calcification (VC) in clinical trials, researchers investigated the impacts of apabetalone on pro-calcific processes because VC contributes to MACE. They observed extracellular calcium deposition was inhibited by apabetalone as well as it opposed induction of transdifferentiation markers in human coronary artery vascular smooth muscle cells (VSMCs) under osteogenic culture conditions. In primary human hepatocytes, downregulation of tissue-nonspecific alkaline phosphatase (TNAP) expression by apabetalone was also seen. Also, apabetalone reduced the size of BRD4-rich enhancers, consistent with disrupting BRD4 association with chromatin. Overall, through an epigenetic mechanism involving specific transcription factors, apabetalone was shown to counter transdifferentiation and calcification of VSMCs. Further development of apabetalone as a therapeutic for VC was supported in the light of mechanistic findings, combined with evidence from clinical trials.