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aDepartment of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan bDepartment of Neurology, Molecular Medicine Laboratory, Taipei Municipal Jen-Ai Hospital, Taipei, Taiwan cInstitute of Neuroscience, Tzu Chi University, Hualien, Taiwan dDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA eStroke Center, Taipei Medical University, Taipei, Taiwan
Address for correspondence: Chung Y. Hsu, M.D., Ph.D., Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan. Voice: +886-2-27361661-2016; fax: +886-2-23787795. hsuc{at}tmu.edu.tw
Ceramide is a pro-apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF-
 /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.
Key Words: ceramide • reactive oxidative species • apoptosis • endothelium • HMG-CoA reductase inhibitors • pravastatin • vascular endothelial growth factor • hypoxia-inducible factor
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