Synthesis of Sphingosine Is Essential for Oxidative Stress-Induced Apoptosis of Photoreceptors
| Autor: | Daniela L. Agnolazza, Nora P. Rotstein, Carolina E. Abrahan, Luis E. Politi, Gisela Edit Miranda |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Paraquat
Ceramide Docosahexaenoic Acids genetic structures Palmitic Acid Sphingosine kinase Apoptosis medicine.disease_cause chemistry.chemical_compound Sphingosine In Situ Nick-End Labeling medicine Animals Enzyme Inhibitors Rats Wistar Cells Cultured Membrane Potential Mitochondrial chemistry.chemical_classification Reactive oxygen species biology Cytochrome c Cytochromes c Oxidants Sphingolipid Rats Cell biology Oxidative Stress Phosphotransferases (Alcohol Group Acceptor) Microscopy Fluorescence chemistry Biochemistry biology.protein sense organs Lysophospholipids Reactive Oxygen Species Oxidative stress Photoreceptor Cells Vertebrate |
| Zdroj: | Investigative Opthalmology & Visual Science. 51:1171 |
| ISSN: | 1552-5783 |
| DOI: | 10.1167/iovs.09-3909 |
| Popis: | Purpose Oxidative stress is involved in inducing apoptosis of photoreceptors in many retinal neurodegenerative diseases. It has been shown that oxidative stress increases in photoreceptors the synthesis of ceramide, a sphingolipid precursor that then activates apoptosis. In several cell types, ceramide is converted by ceramidases to sphingosine (Sph), another apoptosis mediator; hence, this study was undertaken to determine whether Sph participates in triggering photoreceptor apoptosis. Methods Rat retina neurons were incubated with [(3)H]palmitic acid and treated with the oxidant paraquat (PQ) to evaluate Sph synthesis. Sph was added to cultures with or without docosahexaenoic acid (DHA), the major retina polyunsaturated fatty acid and a photoreceptor survival factor, to evaluate apoptosis. Synthesis of Sph and sphingosine-1-phosphate (S1P), a prosurvival signal, were inhibited with alkaline ceramidase or sphingosine kinase inhibitors, respectively, before adding PQ, C(2)-ceramide, or Sph. Apoptosis, mitochondrial membrane polarization, cytochrome c localization, and reactive oxygen species (ROS) production were determined. Results PQ increased [(3)H]Sph synthesis in photoreceptors and blocking this synthesis by inhibiting alkaline ceramidase decreased PQ-induced apoptosis. Addition of Sph induced photoreceptor apoptosis, increased ROS production, and promoted cytochrome c release from mitochondria. Although DHA prevented this apoptosis, inhibiting Sph conversion to S1P blocked DHA protection. Conclusions These results suggest that oxidative stress enhances formation of ceramide and its subsequent breakdown to Sph; ceramide and/or Sph would then trigger photoreceptor apoptosis. Preventing Sph synthesis or promoting its phosphorylation to S1P rescued photoreceptors, suggesting that Sph is a mediator of their apoptosis and modulation of Sph metabolism may be crucial for promoting photoreceptor survival. |
| Databáze: | OpenAIRE |
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