BET inhibitors in cardiovascular diseases: from atherosclerosis to heart failure.

Bromodomain and extra-terminal domain (BET) proteins act as acetyl lysine ‘readers’ that summon transcriptional factors and regulate gene expression. Deregulation of bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, is associated with increased epithelial-mesenchymal transition and profibrotic changes in the cardiovascular system. Consistently, BET inhibitors were shown to attenuate cardiac and vascular remodeling induced through several signaling pathways. BRD4 upregulation has been reported in essential hypertension, dyslipidemia, myocardial infarction, heart failure, pulmonary arterial hypertension (PAH), dilated cardiomyopathy, and diabetic cardiomyopathy. Interestingly, BET inhibitors were found to lower blood pressure, downregulate low-density lipoprotein (LDL), oxidative stress markers, and inflammatory cytokine levels, upregulate high-density lipoprotein (HDL), and prevent pathologic cardiac dysfunction and hypertrophy in animal studies. Furthermore, BET inhibition improved heart transplant survival and hindered neointima formation or vascular remodeling in vivo. Moreover, compared to placebo, apabetalone, a selective bromodomain 2 (BD2) inhibitor, improved cardiovascular outcomes in some clinical trials. These promising findings warrant further studies on the efficacy and safety of BET inhibitors for cardiovascular diseases. This review aimed to discuss the efficacy of BET inhibitors for cardiovascular diseases and unravel the underlying mechanisms.