Epigenetic inhibitors attenuate pathological gene expression in cardiomyocytes

Epigenetic modulators have been proposed as promising new drug targets to treat adverse remodeling in heart failure. Here, we evaluated the potential of 4 epigenetic drugs, including the pan-BRD (bromodomain-containing protein) inhibitor bromosporine, the BET (bromodomain and extraterminal) inhibitor JQ1, the broad-spectrum HDAC inhibitor SAHA, and THE recently developed HDAC6 inhibitor JS28 to prevent endothelin-1 induced pathological gene expression in cardiac myocytes. Although the 4 compounds were similarly effective toward pathological gene expression, JS28 demonstrated the least adverse effects on physiological gene expression. Genome-wide chromatin binding profiles revealed that HDAC6 binding sites were preferentially associated with promoters of genes involved in RNA processing. The distinct chromatin binding profiles of HDAC6 and BRD4 might explain the different effects of their inhibitors on pathological and physiological gene expression. Selective HDAC6 inhibition by JS28 appears to be a promising strategy for future evaluation in vivo and potential translation into clinical application.

Ngo et al. JAHA 2022 https://doi.org/10.1161/jaha.122.025857