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Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and
Jui-Sheng Wu1, Wai-Mui Cheung, Yau-Sheng Tsai
1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Circulation
|February 18, 2009
Summary
Thiazolidinediones protect against brain injury by activating peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This activation increases 14-3-3epsilon, which reduces neuronal apoptosis and cerebral infarction.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Thiazolidinediones are known to protect against ischemia-reperfusion injury.
- Their protective effects are linked to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation.
- The precise mechanism by which PPAR-gamma activation confers protection remains unclear.
Purpose of the Study:
- To investigate the role of PPAR-gamma activation in protecting against cerebral infarction.
- To elucidate the molecular mechanisms underlying the protective effects of PPAR-gamma in neuronal cells.
- To evaluate the therapeutic potential of targeting the PPAR-gamma pathway.
Main Methods:
- Utilized a rat model of cerebral infarction and N2-A neuroblastoma cells.
- Administered rosiglitazone or employed PPAR-gamma overexpression.
- Investigated the effects of PPAR-gamma small interfering RNA and dominant-negative mutants.
- Performed proteomic analysis, promoter analysis, and chromatin immunoprecipitation.
- Assessed the impact of 14-3-3epsilon modulation on cellular damage and apoptosis.
Main Results:
- Rosiglitazone and PPAR-gamma overexpression significantly reduced infarct volume in rats.
- The protective effects were dependent on PPAR-gamma activation, as shown by abrogation with small interfering RNA and dominant-negative mutants.
- Proteomic analysis revealed upregulation of brain 14-3-3epsilon, which was PPAR-gamma-dependent.
- PPAR-gamma directly bound to the 14-3-3epsilon promoter, increasing its transcription.
- Overexpression of 14-3-3epsilon mimicked the protective effects, while its inhibition abrogated them.
- Elevated 14-3-3epsilon protected mitochondrial membrane potential and enhanced the sequestration of phosphorylated Bad.
Conclusions:
- Ligand-activated PPAR-gamma confers resistance to neuronal apoptosis and cerebral infarction.
- This protection is mediated by the transcriptional upregulation of 14-3-3epsilon.
- 14-3-3epsilon suppresses apoptosis by enhancing the sequestration of phosphorylated Bad, thereby protecting neuronal cells.
