br Acknowledgments Funding for this

Acknowledgments Funding for this study was obtained from the South African Medical Research Council for self-initiated research from November 2012 to April 2015 and the Lily and Ernst Hausmann Research Trust to Bongani Mayosi, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01AI079497) to Tawanda Gumbo.
Introduction Intimal hyperplasia (IH) produces vascular lumen re-narrowing or restenosis, leading to failure of angioplasty or bypass commonly performed to treat cardiovascular disease. Without preventive intervention the incidence of restenosis can reach ~30–50% within 6months after surgery (Jukema et al., 2012). While the etiology of IH is multifactorial, at its center is the transition of vascular smooth muscle ll-37 Supplier (SMCs) from quiescence to a proliferative and migratory cell state (Alexander and Owens, 2012). It has become recognized that this SMC phenotypic transition or switching is prompted by abnormalities in chromatin remodeling (Alexander and Owens, 2012). Aside from epigenetic writers (histone acetyl transferases) and erasers (histone deacetylases), there has emerged a new family of epigenetic readers, the bromo and extra-terminal domain (BET) proteins (Gillette and Hill, 2015). The BET family comprises BRDT, BRD2, BRD3, and BRD4 (Shi and Vakoc, 2014). BRDT is testis-specific and hence irrelevant in the vascular system. Each BET protein contains tandem bromodomains that “read” (or bind) acetylated histones. In contrast to BRD2 and BRD3, BRD4 is unique in that it has a C-terminal domain to recruit the positive transcription elongation factor (p-TEFb) to paused RNA polymerase II activating transcriptional elongation (so-called pause release) (Shi and Vakoc, 2014; Kanno et al., 2014). Thus BRD4 “translates” chromatin remodeling to gene transcription. BET epigenetic readers were traditionally deemed undruggable. However, a recent serendipitous discovery of a BET-specific bromodomain blocker (JQ1(+)) (Filippakopoulos et al., 2010), and subsequently its derivatives, have dramatically changed this view(Wang and Filippakopoulos, 2015). Intriguingly, blockade of BRD4 — a general transcription co-activator, does not suppress gene transcription globally, but rather, selectively inhibits the expression of a subset of overactive genes that are often associated with disease states (Wang and Filippakopoulos, 2015, Anand et al., 2013). The key of this selectivity may lie in clusters of transcription enhancers termed super-enhancers (Loven et al., 2013). Upon pathogenic stimulation, super-enhancers re-assemble at a defined set of genes and recruit BRD4 for transcriptional activation of these genes driving cell state transition (Amaral and Bannister, 2014; Brown et al., 2014). This notion has gained strong support from chemical genetic studies using JQ1(+) to inhibit cancer cell proliferation (Asangani et al., 2014; Loven et al., 2013), cardiomyocyte hypertrophy (Anand et al., 2013), and endothelial cell inflammation (Brown et al., 2014). The primary cause of IH is the phenotypic transition of SMCs from a quiescent to a proliferative/migratory cell state, which involves active transcription of a subset of genes, such as growth factors and cytokines and/or their receptors (Alexander and Owens, 2012). We thus hypothesized that the BET epigenetic readers may play a critical role in this cell state transition (Wang et al., 2015), in particular, activation of the platelet-derived growth factor (PDGF) pathway — the most potent stimulant for vascular SMC proliferation and migration (Heldin and Westermark, 1999). Blocking BET bromodomains with JQ1(+) has exhibited high preclinical efficacy in a growing number of malignancies (Zuber et al., 2011; Delmore et al., 2011; Brown et al., 2014; Anand et al., 2013). However, the function of the BET family in restenotic vascular disease is not known. This study aimed to assess whether the BET family plays an important role in the development of IH.