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Peroxisome proliferator-activated receptor agonists prevent 25-OH-cholesterol induced c-jun activation and cell death
1Department of Anatomy & Neurobiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. changjasony@uams.edu
Background:
Cholesterol oxides, the oxygenated derivatives of cholesterol, have been shown to cause programmed cell death in a variety of cell types. Using N9 microglia, this study was designed to investigate the molecular events induced by cholesterol oxides prior to the execution of programmed cell death.
Results:
Microglia were very sensitive to 25-OH-cholesterol, such that a 2-day treatment of the cells with 5 microM 25-OH-cholesterol reduced cell viability to 5-10% of controls. There was a dose- and time-dependent increase in c-jun and phospho-c-jun levels in microglia prior to this 25-OH-cholesterol induced cell death. In contrast, 7-beta-OH-cholesterol, which was relatively non-toxic to microglia, did not increase phospho-c-jun levels. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that have important roles in atherogenesis. Results from this study indicate that PPAR agonists such as 15d-PGJ2, indomethacin and WY14643 can attenuate cholesterol oxide induced c-jun activation and cell death in microglia.
Conclusions:
Peroxisome proliferator-activated receptor agonists may be useful in future development of pharmacological agents against cholesterol oxide induced cytotoxicity.
Insights
Cholesterol oxides induce cell death in microglia by activating c-jun. Peroxisome proliferator-activated receptor (PPAR) agonists protect against this cytotoxicity, suggesting potential therapeutic applications.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Cholesterol oxides, derived from cholesterol, trigger programmed cell death in various cell types.
- N9 microglia are utilized to explore molecular events preceding cholesterol oxide-induced cell death.
Purpose of the Study:
- Investigate molecular mechanisms of cholesterol oxide-induced programmed cell death in N9 microglia.
- Determine the role of c-jun activation and the potential protective effects of PPAR agonists.
Main Methods:
- Treatment of N9 microglia with 25-hydroxycholesterol (25-OH-cholesterol) and 7-beta-hydroxycholesterol.
- Assessment of cell viability, c-jun, and phospho-c-jun levels.
- Evaluation of the effects of PPAR agonists (15d-PGJ2, indomethacin, WY14643).
Main Results:
- 25-OH-cholesterol significantly reduced microglia viability in a dose- and time-dependent manner.
- Cholesterol oxide treatment increased c-jun and phospho-c-jun levels, correlating with cell death.
- PPAR agonists attenuated cholesterol oxide-induced c-jun activation and cytotoxicity.
Conclusions:
- PPAR agonists demonstrate protective effects against cholesterol oxide-induced cell death in microglia.
- PPAR agonists show potential as therapeutic agents for cholesterol oxide-related cytotoxicity.