title: Systemic Acyl-CoA:cholesterol acyltransferase inhibition reduces inflammation and improves vascular function in hypercholesterolemia.
abstract: BACKGROUND
  Circulating lipids may initiate and progress atherosclerosis by causing vascular inflammation. Monocytes and tissue macrophages are involved and regulate lipid metabolism in the vascular wall through acetylation of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT). ACAT inhibition reduces atherosclerosis in animal models by mechanisms that may be independent of their effects on circulating lipids. Because endothelial dysfunction is an important factor in atherosclerosis, we tested the hypothesis that systemic ACAT inhibition would improve endothelial function in hypercholesterolemic humans and assessed its effects on circulating lipids and markers of systemic inflammation.
  
  
  RESULTS
  We studied 21 hypercholesterolemic subjects in a double-blind, randomized-crossover, placebo-controlled trial with assessments of circulating lipids, markers of inflammation, resistance-vessel endothelial function (with venous occlusion plethysmography), and conduit-vessel vasoreactivity (brachial artery flow-mediated dilation at baseline and after placebo or treatment with avasimibe 750 mg QDS for 8 weeks. There was a small change in total cholesterol with treatment (326+/-25 to 311+/-22 mg/dL, P=0.04). Circulating tumor necrosis factor-alpha was significantly reduced (4.0+/-0.3 to 3.6+/-0.2 pg/mL, P=0.02); resistance vessel responses to acetylcholine, bradykinin, and verapamil were significantly enhanced; and responses to nitroglycerin and conduit-vessel vasoreactivity were unchanged after ACAT inhibition.
  
  
  CONCLUSIONS
  Systemic ACAT inhibition reduces circulating tumor necrosis factor-alpha levels in hypercholesterolemic subjects and improves resistance-vessel endothelial function, with small effects on circulating cholesterol. This may be a novel therapeutic strategy to target vascular inflammation and endothelial dysfunction in atherosclerosis.
authors.affiliation: Vascular Physiology Unit, ICH and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kharbanda
authors.forename: Sharon
authors.initials: S
authors.lastname: Wallace
authors.forename: Benjamin
authors.initials: B
authors.lastname: Walton
authors.forename: Ann
authors.initials: A
authors.lastname: Donald
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Cross
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
mesh_terms: D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001783:Blood Flow Velocity / Q000502:physiology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology; D007249:Inflammation / Q000097:blood / Q000201:enzymology; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010991:Plethysmography / Q000379:methods; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
chemical_list: D000214:Acyl Coenzyme A; D015415:Biomarkers; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D002785:Sterol O-Acyltransferase