Effects of an anti-oxidative ACAT inhibitor on apoptosis/necrosis and cholesterol accumulation under oxidative stress in THP-1 cell-derived foam cells.
THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu2+). 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 Cu2+, 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 Cu2+, which was suppressed by KY-455 and YM-750. Foam cells showed necrotic changes and died in the presence of acLDL and Cu2+. 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 Cu2+. 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.
Miike
Tomohiro
T
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto 604-8444, Japan.
Shirahase
Hiroaki
H
Jino
Hiroshi
H
Kunishiro
Kazuyoshi
K
Kanda
Mamoru
M
Kurahashi
Kazuyoshi
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D019327:Copper Sulfate / Q000494:pharmacology; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D008077:Lipoproteins, LDL; C483406:N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide; D017392:Thiobarbituric Acid Reactive Substances; C032629:acetyl-LDL; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D019327:Copper Sulfate; D001205:Ascorbic Acid; D011407:Propane