Abstract MP28: The Bet Bromodomain Inhibitor, (+)-JQ1, Inhibits Neointima Formation Following Acute Vascular Injury Via Pten Upregulation

Abstract

The primary aim of this work was to identify compounds that upregulate phosphatase and tensin homolog (PTEN) expression in smooth muscle cells (SMCs), with the expectation that PTEN upregulation would inhibit pathological vascular remodeling by promoting SMC homeostasis. Our recent work demonstrated that PTEN is an important regulator of SMC phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Angiotensin-II-induced pathological vascular remodeling, suggesting that pharmacologic PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Currently, there are few known pharmacologic inducers of PTEN, however, we have shown that (+)-JQ1, which targets the epigenetic reader protein, Brd4, directly activates the PTEN promoter to drive PTEN expression. Mechanistically, our findings suggest that Brd4 inhibition results in p300-mediated hyper-acetylation of the PTEN promoter to increase PTEN transcriptional activity. Administration of (+)-JQ1 or SMC-specific Brd4 deletion inhibited neointima formation following acute carotid artery injury in mice. Using SMC-specific PTEN depletion both in vitro and in vivo, we showed that the observed anti-remodeling, anti-inflammatory effects were PTEN-dependent. Furthermore, we tested the effects of (+)-JQ1 on macrophage polarization, as systemic drug delivery could potentially modulate the phenotype of other resident vascular cells, including macrophages. We found that (+)-JQ1 inhibited bone marrow-derived macrophage polarization towards a pro-inflammatory phenotype, which is notable because vascular inflammation driven by SMC-macrophage cross-talk is known to promote neointima development. Importantly, our findings may hold direct clinical relevance, as BET bromodomain inhibitors related to (+)-JQ1 are currently undergoing clinical trials. These results are significant because they indicate that targeting PTEN upregulation in SMCs is a completely novel approach to inhibit vascular remodeling.