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

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.

• Authors: Ravi Jahagirdar, Haiyan Zhang, Salman Azhar, Jennifer Tobin, Sarah Attwell, Raymond Yu, Jin Wu, Kevin G McLure, Henrik C Hansen, Gregory S Wagner, Peter R Young, Rai Ajit K Srivastava, Norman C W Wong, Jan Johansson
• Journal: Atherosclerosis (Atherosclerosis) Vol. 236 Issue 1 Pg. 91-100 (Sep 2014) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25016363 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoprotein A-I
• Apolipoproteins E
• Cholesterol, HDL
• Cholesterol, LDL
• Cytokines
• Quinazolines
• Quinazolinones
• RNA, Messenger
• apabetalone
• Betaine-Homocysteine S-Methyltransferase

Topics

• Animals
• Aorta (drug effects, metabolism, pathology)
• Aortic Diseases (blood, etiology, pathology, prevention & control)
• Apolipoprotein A-I (blood)
• Apolipoproteins E (deficiency)
• Atherosclerosis (blood, etiology, pathology, prevention & control)
• Betaine-Homocysteine S-Methyltransferase (antagonists & inhibitors)
• 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, complications, diet therapy, drug therapy, genetics)
• Inflammation (blood, prevention & control)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Quinazolines (pharmacology, therapeutic use)
• Quinazolinones
• RNA, Messenger (analysis)
• U937 Cells