title: ACAT inhibition reduces the progression of preexisting, advanced atherosclerotic mouse lesions without plaque or systemic toxicity.
abstract: OBJECTIVE
  Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters in plaque foam cells. Complete deficiency of macrophage ACAT has been shown to increase atherosclerosis in hypercholesterolemic mice because of cytotoxicity from free cholesterol accumulation, whereas we previously showed that partial ACAT inhibition by Fujirebio compound F1394 decreased early atherosclerosis development. In this report, we tested F1394 effects on preestablished, advanced lesions of apolipoprotein-E-deficient mice.
  
  
  RESULTS
  Apolipoprotein-E-deficient mice on Western diet for 14 weeks developed advanced plaques, and were either euthanized (Baseline), or continued on Western diet with or without F1394 and euthanized after 14 more weeks. F1394 was not associated with systemic toxicity. Compared with the baseline group, lesion size progressed in both groups; however, F1394 significantly retarded plaque progression and reduced plaque macrophage, free and esterified cholesterol, and tissue factor contents compared with the untreated group. Apoptosis of plaque cells was not increased, consistent with the decrease in lesional free cholesterol. There was no increase in plaque necrosis and unimpaired efferocytosis (phagocytic clearance of apoptotic cells). The effects of F1394 were independent of changes in plasma cholesterol levels.
  
  
  CONCLUSIONS
  Partial ACAT inhibition by F1394 lowered plaque cholesterol content and had other antiatherogenic effects in advanced lesions in apolipoprotein-E-deficient mice without overt systemic or plaque toxicity, suggesting the continued potential of ACAT inhibition for the clinical treatment of atherosclerosis, in spite of recent trial data.
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Research Program of the Leon H. Charney Division of Cardiology and the Department of Medicine (Cardiology), New York University School of Medicine, Smilow 7, 522 First Ave, New York, NY 10029, USA.
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: Courtney
authors.initials: C
authors.lastname: Blachford
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.forename: Ilda
authors.initials: I
authors.lastname: Bander
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mayne
authors.forename: Jun
authors.initials: J
authors.lastname: Kusunoki
authors.forename: Christine
authors.initials: C
authors.lastname: Miller
authors.forename: Matthew
authors.initials: M
authors.lastname: Davis
authors.forename: Martha
authors.initials: M
authors.lastname: Wilson
authors.forename: Shirley
authors.initials: S
authors.lastname: Dehn
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Mark B
authors.initials: MB
authors.lastname: Taubman
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003510:Cyclohexanes / Q000494:pharmacology*; D004036:Diet, Atherogenic; D004146:Dioxanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D058226:Plaque, Atherosclerotic; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D003510:Cyclohexanes; D004146:Dioxanes; D004791:Enzyme Inhibitors; C094918:F 1394; D013925:Thromboplastin; D002784:Cholesterol; D000102:Acetyl-CoA C-Acyltransferase