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  • Title: Acyl-coenzymeA (CoA):cholesterol acyltransferase inhibition in rat and human aortic smooth muscle cells is nontoxic and retards foam cell formation.
    Author: Rong JX, Kusunoki J, Oelkers P, Sturley SL, Fisher EA.
    Journal: Arterioscler Thromb Vasc Biol; 2005 Jan; 25(1):122-7. PubMed ID: 15499046.
    Abstract:
    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 microg/mL) became foam cells by morphological (oil-red-O staining) and biochemical (approximately 1200% and approximately 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. CONCLUSIONS: ASMC might be more resistant to FC-induced adverse effects than are macrophages.
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