Abstract 194: Inhibition of Epigenetic Reader BRD4 Mitigates Intimal Hyperplasia Following Angioplasty in Rat Carotid Arteries
Background: Intimal hyperplasia (IH) causes recurrent lumen narrowing leading to failure of revascularization. BRD4 represents an emerging class of epigenetic “readers” and has recently been shown to play a crucial role in cancer. While blockage of BRD4 activity with a specific inhibitor (JQ1) rescues heart failure in a mouse model, the role of BRD4 in vascular diseases is not known.
Hypothesis: BRD4 stimulates IH by promoting a transformation of vascular smooth muscle cells (SMCs) from quiescent to proliferative and migratory phenotypes.
Methods and Results: Balloon angioplasty was performed to induce IH in rat carotid arteries. Immunohistochemistry showed that 7 days after balloon injury, 85% of cells in the neointima were BRD4 positive, in contrast this ratio was only 7% in the media of uninjured control (n=3 animals). A pronounced increase of BRD4 was also observed in restenotic versus normal human veins. Blocking BRD4 with periadventitially applied JQ1 (500 μg/rat) reduced IH by 75% and SMC proliferation (PCNA staining) by 60% compared to vehicle control (n=4, p<0.05) at 14 days post injury. Consistently, in vitro treatment with 1 μM JQ1 markedly inhibited PDGF-BB induced proliferation (by 72%) and migration (by 63%) in rat aortic SMCs as well as proliferation in human aortic SMCs (by 56%). Whereas PDGF receptor (PDGFRα) was found to be drastically up-regulated in restenotic versus normal human veins, it was reduced by 55% in JQ1-treated rat carotid arteries compared to vehicle control 14 days after balloon injury (n=4, p<0.05). Accordantly, Western blotting showed a 70% decrease of PDGFRα in cultured rat SMCs 48h after treatment with 1 μM JQ1.
Conclusions: Our study is the first to demonstrate that inhibiting epigenetic reader BRD4 mitigates IH, likely by down-regulating PDGFRα expression. This epigenetic regulation may provide novel targets for effective therapeutic prevention of IH.
Author Disclosures: B. Wang: None. T. Takayama: None. M. Zhang: None. X. Shi: None. D. Roenneburg: None. K. Kent: None. L. Guo: None.
- © 2015 by American Heart Association, Inc.