Blocking BET epigenetic readers with JQ1(+) mitigates neointimal proliferation in balloon-injured rat carotid arteries.
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JQ1(+) or BRD4 knockdown inhibits vascular smooth muscle cell proliferation, migration, and PDGF receptor expression.
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JQ1(+) prevents inflammatory dysfunction of vascular endothelial cells.
The transition of vascular smooth muscle cells to a migratory proliferative state produces a new thick layer of tissue on the inner vessel wall obstructing blood flow. Epigenetic control of this transition is poorly understood. We find that inhibiting a family of epigenetic regulators called “readers” halts this disease-prone process. Our study may open fresh opportunities for epigenetic interventions to prevent smooth muscle cell instability and associated occlusive vascular diseases that pose a great threat to public health.
Abstract
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.
Abbreviations
IH
intimal hyperplasia
SMC
vascular smooth muscle cell
EC
vascular endothelial cells
BET
bromo- and extra-terminal domain family of epigenetic readers
BRD4
bromodomain-containing protein 4, a BET family member