Abstract 10591: Epigenetic BET Reader Inhibitor Apabetalone (RVX-208) Counters Proinflammatory Aortic Gene Expression in a Diet Induced Obesity Mouse Model

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A10591-A10591
• Main Authors: Wasiak, Sylwia, Daze, Emily, Tsujikawa, Laura M, Gilham, Dean, Sarsons, Christopher, Stotz, Stephanie, Rakai, Brooke, Azhar, Salman, Jahagirdar, Ravi, Sweeney, Michael, Johansson, Jan, Wong, Norman, Kulikowski, Ewelina
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.10591

IntroductionObesity increases the risk of type 2 diabetes (DM2) and cardiovascular disease (CVD), due to associated insulin resistance, dyslipidemia, high blood pressure and chronic inflammation. Bromodomain and extraterminal (BET) proteins such as BRD4 enhance the expression of proinflammatory genes by recruiting transcription factors to promoters and enhancers. Inhibition of BET binding to chromatin leads to anti-inflammatory and anti-atherogenic effects in models of DM2 and CVD. HypothesisBET inhibition with apabetalone, a clinical-stage small molecule, reduces vascular inflammation in a mouse model of diet-induced obesity. MethodsFrom 8 to 30 weeks of age, C57 BL/6J mice were fed a high-fat (HFD) or low-fat diet (LFD). Mice received apabetalone at 150 mg/kg b.i.d between 14 and 30 weeks. Gene expression was analyzed post necropsy in the aorta by PCR, nCounter® Inflammation Panel and Ingenuity® Pathway Analysis. Human aortic endothelial cells (HAECs) treated with TNFα and apabetalone were analyzed by BRD4 ChIP-seq and RNA-seq to assess BRD4 chromatin occupancy and transcriptional changes. ResultsProfiling of 254 genes in the aorta showed an upregulation of 27 inflammatory genes in HFD-fed mice as compared to LFD (p