Effects of an anti-oxidative ACAT inhibitor on apoptosis/necrosis and cholesterol accumulation under oxidative stress in THP-1 cell-derived foam cells

• Published in: Life sciences (1973) 2008-01, Vol.82 (1), p.79-84
• Main Authors: Miike, Tomohiro, Shirahase, Hiroaki, Jino, Hiroshi, Kunishiro, Kazuyoshi, Kanda, Mamoru, Kurahashi, Kazuyoshi
• Format: Article
• Language: English
• Subjects: ACAT inhibitor; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis; Apoptosis - drug effects; Ascorbic Acid - pharmacology; Cell Line; Cholesterol; Cholesterol - metabolism; Copper Sulfate - pharmacology; Foam cell; Foam Cells - drug effects; Foam Cells - metabolism; Foam Cells - pathology; Indoles - pharmacology; Lipid Peroxidation - drug effects; Lipoproteins, LDL - pharmacology; Necrosis; Oxidative stress; Oxidative Stress - drug effects; Propane - analogs & derivatives; Propane - pharmacology; Rabbits; Sterol O-Acyltransferase - antagonists & inhibitors; Thiobarbituric Acid Reactive Substances - metabolism; THP-1
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2007.10.011

THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu 2+). The foam cells showed caspase-dependent apoptotic changes on exposure to oxidative stress for 6 h, and necrotic changes with the leakage of LDH after 24 h. KY-455, an anti-oxidative ACAT inhibitor, and ascorbic acid (VC) but not YM-750, an ACAT inhibitor, prevented apoptotic and necrotic changes. These preventive effects of KY-455 and VC were accompanied by the inhibition of lipid peroxidation in culture medium containing acLDL and Cu 2+, suggesting the involvement of oxidized acLDL in apoptosis and necrosis. Foam cells accumulated esterified cholesterol (EC) for 24 h in the presence of acLDL without Cu 2+, which was suppressed by KY-455 and YM-750. Foam cells showed necrotic changes and died in the presence of acLDL and Cu 2+. KY-455 but not YM-750 prevented cell death and reduced the amount of EC accumulated. The foam cells treated with VC further accumulated EC without necrotic changes for 24 h even in the presence of acLDL and Cu 2+. YM-750 as well as KY-455 inhibited lipid accumulation when co-incubated with VC in foam cells exposed to oxidative stress. It is concluded that an anti-oxidative ACAT inhibitor or the combination of an antioxidant and an ACAT inhibitor protects foam cells from oxidative stress and effectively reduces cholesterol levels, which would be a promising approach in anti-atherosclerotic therapy.