This Article Full Text Full Text (PDF) All Versions of this Article: 111/6/804    most recent 01.CIR.0000155236.25081.9Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kharbanda, R. K. Articles by Deanfield, J. Search for Related Content PubMed PubMed Citation Articles by Kharbanda, R. K. Articles by Deanfield, J. Related Collections Cardiovascular Pharmacology Lipid and lipoprotein metabolism Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation. 2005;111:804-807.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Systemic Acyl-CoA:Cholesterol Acyltransferase Inhibition Reduces Inflammation and Improves Vascular Function in Hypercholesterolemia

Rajesh K. Kharbanda, PhD, MRCP; Sharon Wallace, BA; Benjamin Walton, MRCP; Ann Donald, AVS; Jennifer M. Cross, PhD, MRCP; John Deanfield, MA, FRCP

From the Vascular Physiology Unit (R.K.K., S.W., B.W., A.D., J.M.C., J.D.), ICH and Great Ormond Street Hospital for Children NHS Trust, Centre for Clinical Pharmacology (R.K.K., J.M.C.), British Heart Foundation Laboratories, University College London, London, United Kingdom.

Correspondence to John Deanfield, Institute of Child Health, 30 Guilford St, London, WC1N 1EH, United Kingdom. E-mail J.Deanfield{at}ich.ucl.ac.uk

Received June 24, 2004; revision received October 10, 2004; accepted October 15, 2004.

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.

Methods and 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- 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- 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.

Key Words: endothelium • hypercholesterolemia • inflammation

This article has been cited by other articles:

				M. Y.K. Lee, H.-F. Tse, C.-W. Siu, S.-G. Zhu, R. Y.K. Man, and P. M. Vanhoutte Genomic Changes in Regenerated Porcine Coronary Arterial Endothelial Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2443 - 2449. [Abstract] [Full Text] [PDF]

				K. M. Maki-Petaja, A. D. Booth, F. C. Hall, S. M.L. Wallace, J. Brown, C. M. McEniery, and I. B. Wilkinson Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis J. Am. Coll. Cardiol., August 28, 2007; 50(9): 852 - 858. [Abstract] [Full Text] [PDF]