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PPARalpha-mediated upregulation of uncoupling protein-2 switches cyanide-induced apoptosis to necrosis in primary cortical cells.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2006 Sep; Vol. 93 (1), pp. 136-45. Date of Electronic Publication: 2006 Jun 16. - Publication Year :
- 2006
-
Abstract
- Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear factor PPAR family that regulates a variety of cellular functions, including lipid metabolism, cellular oxidative stress defense, and inflammatory responses. Based on the report that Wy14,643, a PPARalpha agonist, can upregulate uncoupling protein-2 (UCP-2), this study was conducted in primary cortical cells to determine if PPARalpha activation enhances cyanide-induced neurotoxicity through changes in the level of UCP-2. PCR and Western blot analysis showed that Wy14,643 upregulated UCP-2 transcriptionally over a 12-h period. This response was mediated by PPARalpha since it was blocked by MK886, a selective PPARalpha antagonist. The effect of UCP-2 upregulation on the cytotoxic response to cyanide was quantitated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (apoptosis) and propidium iodide staining (necrosis). Wy14,643 switched the mode of cyanide-induced cell death from apoptosis to necrosis. Cell death was preceded by marked mitochondrial dysfunction, as reflected by depletion of ATP and reduction of the mitochondrial membrane potential (DeltaPsim). Knock down of UCP-2 expression by RNA interference blocked the Wy14,643-mediated enhancement of cyanide-induced mitochondrial dysfunction and the switch of the cell death mode, thus confirming that the response was mediated by upregulation of UCP-2. This study shows that PPARalpha activation can upregulate UCP-2 expression, which in turn enhances cyanide-induced necrotic cell death through an increase of mitochondrial dysfunction.
- Subjects :
- Animals
Base Sequence
DNA Primers
Necrosis
Pyrimidines pharmacology
RNA, Small Interfering
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Uncoupling Protein 2
Apoptosis drug effects
Cyanides pharmacology
Ion Channels physiology
Mitochondrial Proteins physiology
PPAR alpha physiology
Up-Regulation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-6080
- Volume :
- 93
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 16782780
- Full Text :
- https://doi.org/10.1093/toxsci/kfl039