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


      • We report effect of a novel BET inhibitor RVX-208 in hyperlipidemic apoE−/− mice.
      • We examined effect of RVX-208 in prophylactic and therapeutic regimen.
      • RVX-208 significantly increased HDL-c and decreased LDL-c.
      • RVX-208 significantly decreased circulating cytokine and expression of aortic inflammatory genes.
      • RVX-208 was well tolerated at the doses evaluated.


      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.



      apoA-I (apolipoprotein A-I), BET (bromodomain and extra terminal), CVD (cardiovascular disease), CAD (coronary artery disease), ChreBP (carbohydrate response element binding protein), HDL (high-density lipoprotein), HMG-CoA (hydroxymethylglutarate coenzyme A), Hp (haptoglobin), HPL-C (high performance liquid chromatography), HAEC (Human Aortic endothelial cells), ICAM-1 (intercellular adhesion molecule 1), IL-6 (interleukin 6), IP-10 (interferon gamma inducible protein 10), LDL (low-density lipoprotein), MCP-1 (macrophage chemo-attractant protein 1), MIP1 (macrophage inflammatory protein 1), TG (triglycerides), VCAM-1 (vascular cell adhesion molecule 1)
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