A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice

• Published in: Atherosclerosis Vol. 236; no. 1; pp. 91 - 100
• Main Authors: Jahagirdar, Ravi, Zhang, Haiyan, Azhar, Salman, Tobin, Jennifer, Attwell, Sarah, Yu, Raymond, Wu, Jin, McLure, Kevin G, Hansen, Henrik C, Wagner, Gregory S, Young, Peter R, Srivastava, Rai Ajit K, Wong, Norman C.W, Johansson, Jan
• Format: Journal Article
• Language: English
• Published: Ireland 01.09.2014
• Subjects: Animals; Aorta - drug effects; Aorta - metabolism; Aorta - pathology; Aortic Diseases - blood; Aortic Diseases - etiology; Aortic Diseases - pathology; Aortic Diseases - prevention & control; Apolipoprotein A-I - blood; Apolipoproteins E - deficiency; Atherosclerosis - blood; Atherosclerosis - etiology; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Betaine-Homocysteine S-Methyltransferase - antagonists & inhibitors; Cardiovascular; Cell Line; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Cytokines - blood; Diet, Fat-Restricted; Diet, Western - adverse effects; Drug Evaluation, Preclinical; Endothelial Cells; Gene Expression Profiling; Humans; Hyperlipidemias - blood; Hyperlipidemias - complications; Hyperlipidemias - diet therapy; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; Inflammation - blood; Inflammation - prevention & control; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Quinazolines - pharmacology; Quinazolines - therapeutic use; RNA, Messenger - analysis; U937 Cells; coronary artery disease; MCP-1; macrophage inflammatory protein 1; ChreBP; high-density lipoprotein; interferon gamma inducible protein 10; ICAM-1; apolipoprotein A-I; intercellular adhesion molecule 1; HDL; interleukin 6; apoE deficient; LDL; Atherosclerosis; hydroxymethylglutarate coenzyme A; MIP1; BET inhibitor; vascular cell adhesion molecule 1; carbohydrate response element binding protein; Human Aortic endothelial cells; haptoglobin; macrophage chemo-attractant protein 1; cardiovascular disease; HPL-C; CAD; Hp; HMG-CoA; Inflammation; triglycerides; RVX-208; IP-10; bromodomain and extra terminal; IL-6; low-density lipoprotein; BET; CVD; high performance liquid chromatography; VCAM-1; TG; Preβ-HDL; HAEC; apoA-I-inducer; apoA-I
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2014.06.008

Abstract Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE−/− mice. Oral treatments of apoE−/− mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ∼50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin, a proinflammatory protein, known to bind with HDL/apoA-I, decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10, MIP1® and MDC. These results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities.