Pravastatin attenuates ceramide-induced cytotoxicity in mouse cerebral endothelial cells with HIF-1 activation and VEGF upregulation

Shang Der Chen, Chaur Jong Hu, Ding I. Yang, Abdullah Nassief, Hong Chen, Kejie Yin, Jan Xu, Chung-Yi Hsu

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 languageEnglish
Pages (from-to)357-364
Number of pages8
JournalAnnals of the New York Academy of Sciences
Volume1042
DOIs
Publication statusPublished - 2005

Keywords

  • Apoptosis
  • Ceramide
  • Endothelium
  • HMG-CoA reductase inhibitors
  • Hypoxia-inducible factor
  • Pravastatin
  • Reactive oxidative species
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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