Background: Intimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic "readers" including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known.
Methods: We investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model.
Results: While BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(-), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(-), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced.
Conclusions: Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.
Keywords: BET; BET, bromo- and extra-terminal domain family of epigenetic readers; BRD4; BRD4, bromodomain-containing protein 4, a BET family member; EC, vascular endothelial cells; Epigenetic reader; IH, intimal hyperplasia; Intimal hyperplasia; JQ1(+), a BET-specific bromodomain inhibitor; JQ1(−), inactive enantiomer; PDGF, platelet-derived growth factor; SMC, vascular smooth muscle cell; Smooth muscle cell.