Epigenetic BET reader inhibitor apabetalone (RVX-208) counters proinflammatory aortic gene expression in a diet induced obesity mouse model and in human endothelial cells

Approximately 39%–49% of the world's population (2.8–3.5 billion people) is overweight or obese [1], resulting in an increased risk of dyslipidemia, type 2 diabetes (T2DM), hypertension, and cardiovascular disease (CVD) [2]. Obese patients experience cardiovascular events at an earlier age, live with CVD for a greater proportion of their lifetime, and have a shorter average life span than individuals with normal weight [3]. Indeed, obesity is the most common nonischemic cause of sudden cardiac death [4], with risk increasing 16% for every 5-unit increment in BMI [5]. Thus, there is a distinct need for efficacious drugs to prevent the progression of CVD in obese patients.

Bromodomain and extra-terminal protein (BET) inhibition represents a novel, epigenetic approach to lowering CVD risk [6]. Ubiquitously expressed BET proteins BRD2, BRD3 and BRD4 play a role in chromatin organization and gene transcription. BET proteins have two bromodomains (BD1 and BD2) that bind acetylated lysine residues on histones and transcription regulators [7]. As scaffolding proteins, BETs link acetylated chromatin and chromatin bound factors to transcription machinery at gene regulatory elements, thus facilitating gene expression. Extrinsic and intrinsic factors such as disease history, environmental cues and lifestyle choices can alter the chromatin epigenetic profile in CVD patients, enabling epigenetic readers such as BET proteins to activate disease-driving genes [8]. The resulting changes in protein expression promote cellular dysfunction that underlies cardiomyopathies, heart failure, cardiac fibrosis, hypertension and atherosclerosis [8]. BET inhibitors (BETi) bind to BET bromodomains, competitively inhibit interactions with acetylated lysine residues and block downstream transcription events [9,10]. Chemical compounds that have equal affinity for BET BD1 and BD2 (termed pan-BETi) display broad transcriptional effects and are primarily in development for oncology indications, as they target genes responsible for cell growth and viability [11,12]. In contrast, BD2-selective BETi are effective at reducing the transcriptional response to inflammation, without impacting cell survival pathways [12], making them attractive therapeutics for chronic indications such as obesity, T2DM and CVD.

The pathophysiology of obesity has been replicated in the diet induced obesity (DIO) mouse model [13], enabling in vivo evaluation of candidate therapeutics. Mice quickly gain weight on a high-fat diet (HFD), with dyslipidemia, hyperglycemia, hyperinsulinemia, and chronic inflammation developing in weeks [14]. Dyslipidemia causes lipid accumulation in the arterial wall and endothelial expression of chemokines and cellular adhesion molecules, which attract monocytes and allow them to transmigrate across the endothelial monolayer [13]. Transmigrating monocytes differentiate into macrophages, scavenge lipoproteins, and turn into foam cells, which form early atherosclerotic plaques and further promote lipoprotein retention, inducing a cascade of inflammatory responses [15]. Atherosclerosis can be exacerbated by combining HFD with the genetic deficiency of apolipoprotein E (Apoe−/−) or low-density lipoprotein receptor-deficient (Ldlr−/−) [16].Treatment of HFD-fed Apoe−/− mice with the BD2-selective BETi apabetalone was reported to decrease atherosclerotic lesions in the whole aorta and the aortic sinus, blood cytokine levels (Cxcl10, Ccl4 and Ccl22) and aortic gene expression of proinflammatory cytokines (Il6, Ccl2) and adhesion molecules (Icam1, Vcam1) [17]. Similar effects were observed following pan-BETi JQ1 treatment of Ldlr−/− mice [18]. These results correlate with clinical findings as treatment of coronary artery disease (CAD) patients with apabetalone significantly reduced both atherosclerotic plaque size and vulnerability [19]. CAD patients also had fewer circulating proteins that promote vascular inflammation and plaque instability following apabetalone treatment [20]. Here, we compare apabetalone, a phase 3 clinical trial BETi candidate for the secondary prevention of major adverse cardiovascular events in patients at high risk for CVD [[21], [22], [23]], and JQ1, a high potency experimental BETi [18,24], in the DIO mouse model on a high-fat low-cholesterol diet, to evaluate the potential of BETi to counter vascular inflammation in the context of obesity. We also characterize proinflammatory signaling in human aortic endothelial cells in response to TNFα and BETi.

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