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Atherosclerosis. 2014 Sep;236(1):91-100. doi: 10.1016/j.atherosclerosis.2014.06.008. Epub 2014 Jun 28.

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

Author information

1
Resverlogix Corp., Calgary, Canada. Electronic address: ravi@resverlogix.com.
2
VA Palo Alto Health Care System, Palo Alto, USA.
3
Resverlogix Corp., Calgary, Canada.
4
Integrated Pharma Solutions, Philadelphia, USA.

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.

KEYWORDS:

Atherosclerosis; BET inhibitor; Inflammation; Preβ-HDL; RVX-208; apoA-I-inducer; apoE deficient

[Indexed for MEDLINE]

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