Peroxisome proliferator-activated receptor agonists prevent 25-OH-cholesterol induced c-jun activation and cell death.
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.
Chang
J Y
JY
Department of Anatomy & Neurobiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. changjasony@uams.edu
Liu
L Z
LZ
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists*
D006888:Hydroxycholesterols; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C007997:25-hydroxycholesterol; D020928:Mitogen-Activated Protein Kinases; D007213:Indomethacin