Pravastatin attenuates ceramide-induced cytotoxicity in mouse cerebral endothelial cells with HIF-1 activation and VEGF upregulation.
Ceramide is a pro-apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF-alpha/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 microM. 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 microM 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.
Chen
Shang-Der
SD
Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Hu
Chaur-Jong
CJ
Yang
Ding-I
DI
Nassief
Abdullah
A
Chen
Hong
H
Yin
Kejie
K
Xu
Jan
J
Hsu
Chung Y
CY
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D002518:Ceramides; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D004247:DNA; D017035:Pravastatin