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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:122.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Acyl-CoenzymeA (CoA):Cholesterol Acyltransferase Inhibition in Rat and Human Aortic Smooth Muscle Cells Is Nontoxic and Retards Foam Cell Formation

James X. Rong; Jun Kusunoki; Peter Oelkers; Stephen L. Sturley; Edward A. Fisher

From Marc and Ruti Bell Vascular Biology Research Program of the Leon H. Charney Division of Cardiology (Department of Medicine) and the Department of Cell Biology (J.X.R., J.K., E.A.F.), New York University School of Medicine, New York, NY; and the Institute of Human Nutrition (P.O., S.L.S.) and the Department of Pediatrics (S.L.S.), Columbia University, New York, NY.

Correspondence to Edward A. Fisher, MD, PhD, TH-451, NYU School of Medicine, 550 1st Avenue, New York, NY 10016. E-mail edward.fisher{at}med.nyu.edu

Objective— Studies in vitro and in vivo of macrophage foam cells have shown evidence of cytotoxicity after acyl-CoA:cholesterol acyltransferase (ACAT) inhibition. Foam cells of smooth muscle origin are also found in human and animal atherosclerotic lesions.

Methods and Results— To study whether cytotoxicity from ACAT inhibition is independent of cell type, we first established a protocol to conveniently induce aortic smooth muscle foam cell formation using cholesterol–cyclodextrin complexes (CCC). Rat aortic smooth muscle cells (ASMCs) treated for 48 hours with CCC (20 µg/mL) became foam cells by morphological (oil-red-O staining) and biochemical (1200% and 180% increase in cellular esterified and free cholesterol, respectively) criteria. ACAT activity increased 500% (P<0.01 versus untreated). Similar results were obtained in human ASMC, but ACAT activity increased to an even greater extent (3200%; P<0.01 versus untreated). Western blots indicated that CCC treatment increased human (to 380±20% of untreated, P<0.001), but not rat, ACAT protein expression. ACAT inhibition by Fujirebio compound F1394 suppressed CCC-induced foam cell formation in rat and human ASMC, but, notably, did not induce significant cytotoxicity.

Conclusion— ASMC might be more resistant to FC-induced adverse effects than are macrophages.

Aortic smooth muscle foam cell formation was induced with cholesterol–cyclodextrin complexes. Compared with current and published data in macrophages, simultaneous cholesterol-loading and ACAT inhibition led to little cytotoxicity in SMCs. Therefore, the potential for adverse consequences of ACAT inhibitors used therapeutically may be related to dose and the cell type.

Key Words: cyclodextrins • F1394 • lipid droplets • smooth muscle cells • ACAT

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Sergio Fazio, Dwayne E. Dove, and MacRae F. Linton
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