Abstract
BackgroundIntimal 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. MethodsWe investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model. ResultsWhile 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. ConclusionsBlocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.
Highlights
Intimal hyperplasia (IH) produces vascular lumen re-narrowing or restenosis, leading to failure of angioplasty or bypass commonly performed to treat cardiovascular disease
bromodomain-containing protein 4 (BRD4) is the best characterized bromo and extra-terminal (BET) member and has been shown to play a pivotal role in several disease states (Anand et al, 2013; Wang and Filippakopoulos, 2015). It is a unique BET member in that it is associated with super-enhancers and its C-terminal domain facilitates the recruitment of the positive transcription elongation factor p-TEFb to activate RNA polymerase II (Anand et al, 2013; Kanno et al, 2014)
While the expression of BRD4 in the media declined after day 3, concomitantly BRD4-positive cells dramatically increased in the neointima with a ratio of 85% versus total cells at day 7, and remained at 55% at day 14
Summary
Intimal hyperplasia (IH) produces vascular lumen re-narrowing or restenosis, leading to failure of angioplasty or bypass commonly performed to treat cardiovascular disease. 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. Conclusions: Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases
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