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Pravastatin Attenuates Ceramide-Induced Cytotoxicity in Mouse Cerebral Endothelial Cells with HIF-1 Activation and VEGF Upregulation

机译:普伐他汀在小鼠脑内皮细胞中衰减宫胺诱导的细胞毒性,HIF-1活化和VEGF上调

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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 C_2 ceramide for 12 h caused cell death in a concentration-dependent manner, with a LC_(50) 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.
机译:神经酰胺是一种促凋亡脂质信使,可诱导氧化应激,并且可以在TNF /环己酰亚胺,脂多糖,氧化LDL,IL-1和淀粉样肽诱导的脑内皮细胞(CEC)中介导细胞凋亡。 CEC的暴露于C_2神经酰胺12小时,以浓度依赖性方式导致细胞死亡,LC_(50)为30μm。他汀汀是3-羟基-3-甲基辅酶的抑制剂是还原酶,其是胆固醇生物合成的速率限制酶。用20μm的普伐他汀预处理16小时,在小鼠CEC中基本上减弱神经酰胺细胞毒性。在普伐他汀治疗后1-3小时内检测血管内皮生长因子(VEGF)表达的增加。该普伐他汀作用伴有缺氧诱导因子-1(HIF-1)的激活,已知已知活化VEGF表达的转录因子。这些结果提高了普伐他汀可以通过HIF-VEGF级联来保护CEC免受神经酰胺诱导的死亡。

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