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

Abstract

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.

• Authors: Tomohiro Miike, Hiroaki Shirahase, Hiroshi Jino, Kazuyoshi Kunishiro, Mamoru Kanda, Kazuyoshi Kurahashi
• Journal: Life sciences (Life Sci) Vol. 82 Issue 1-2 Pg. 79-84 (Jan 02 2008) ISSN: 0024-3205 [Print] Netherlands
• PMID: 18037448 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Indoles
• Lipoproteins, LDL
• N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide
• Thiobarbituric Acid Reactive Substances
• acetyl-LDL
• Cholesterol
• Sterol O-Acyltransferase
• Copper Sulfate
• Ascorbic Acid
• Propane

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects)
• Ascorbic Acid (pharmacology)
• Cell Line
• Cholesterol (metabolism)
• Copper Sulfate (pharmacology)
• Foam Cells (drug effects, metabolism, pathology)
• Indoles (pharmacology)
• Lipid Peroxidation (drug effects)
• Lipoproteins, LDL (pharmacology)
• Necrosis
• Oxidative Stress (drug effects)
• Propane (analogs & derivatives, pharmacology)
• Rabbits
• Sterol O-Acyltransferase (antagonists & inhibitors)
• Thiobarbituric Acid Reactive Substances (metabolism)