title: 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.affiliation: Resverlogix Corp., Calgary, Canada. Electronic address: ravi@resverlogix.com.
authors.forename: Ravi
authors.initials: R
authors.lastname: Jahagirdar
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, USA.
authors.forename: Salman
authors.initials: S
authors.lastname: Azhar
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tobin
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Attwell
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Yu
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: McLure
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Henrik C
authors.initials: HC
authors.lastname: Hansen
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Wagner
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Young
authors.affiliation: Integrated Pharma Solutions, Philadelphia, USA.
authors.forename: Rai Ajit K
authors.initials: RA
authors.lastname: Srivastava
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.affiliation: Resverlogix Corp., Calgary, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000097:blood; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors*; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D016207:Cytokines / Q000097:blood; D018752:Diet, Fat-Restricted; D066273:Diet, Western / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells; D020869:Gene Expression Profiling; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics; D007249:Inflammation / Q000097:blood / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones; D012333:RNA, Messenger / Q000032:analysis; D020298:U937 Cells
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D016207:Cytokines; D011799:Quinazolines; D052999:Quinazolinones; D012333:RNA, Messenger; C000628794:apabetalone; D050940:Betaine-Homocysteine S-Methyltransferase
keywords: Atherosclerosis; BET inhibitor; Inflammation; Preβ-HDL; RVX-208; apoA-I-inducer; apoE deficient