on October 21, 2004
Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148202.49842.3b
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Submitted on January 20, 2004
Accepted on October 5, 2004
Acyl-CoenzymeA (CoA):Cholesterol Acyltransferase Inhibition in Rat and Human Aortic Smooth Muscle Cells Is Nontoxic and Retards Foam Cell Formation
James X. Rong ;
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 (J.K., S.L.S.), Columbia University, New York, NY.
* To whom correspondence should be addressed. 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.
Conclusions--ACAT inhibition by Fujirebio compound F1394 suppressed CCC-induced foam cell formation in rat and human ASMC, but, notably, did not induce significant cytotoxicity, indicating ASMC might be more resistant to FC-induced adverse effects than are macrophages.
Key words: cyclodextrins • F1394 • lipid droplets • smooth muscle cells • ACAT
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