Abstract
Ceramide is a pro-apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF-α/cycloheximide, lipopolysaccharide, oxidized LDL, IL-1, and amyloid peptide. Exposure of CECs to C2 ceramide for 12 h caused cell death in a concentration-dependent manner, with a LC50 of 30 μM. Statins are inhibitors of 3-hydroxyl-3-methyl coenzyme A reductase which is the rate-limiting enzyme for cholesterol biosynthesis. Pretreatment with pravastatin at 20 μM for 16 h substantially attenuated ceramide cytotoxicity in mouse CECs. Increases in vascular endothelial growth factor (VEGF) expression were detected within 1-3 h after pravastatin treatment. This pravastatin action was accompanied by the activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor known to activate VEGF expression. These results raise the possibility that pravastatin may protect CECs against ceramide-induced death via the HIF-VEGF cascade.
Original language | English |
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Pages (from-to) | 357-364 |
Number of pages | 8 |
Journal | Annals of the New York Academy of Sciences |
Volume | 1042 |
DOIs | |
State | Published - 2005 |
Externally published | Yes |
Keywords
- Apoptosis
- Ceramide
- Endothelium
- HMG-CoA reductase inhibitors
- Hypoxia-inducible factor
- Pravastatin
- Reactive oxidative species
- Vascular endothelial growth factor