Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells
Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells
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DOI：
10.1038/jcbfm.2010.180
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发表时间：
2011-03-01
影响因子：
6.3
通讯作者：
Chen, Ruei-Ming
中科院分区：
文献类型：
--
作者：
Chang, Huai-Chia;Chen, Tyng-Guey;Chen, Ruei-Ming
脑血管内皮细胞（CEC）是血脑屏障的重要组成部分。我们前期的研究表明氧化低密度脂蛋白（oxLDL）可诱导CEC凋亡。本研究旨在进一步探讨白藜芦醇对oxLDL诱导的CEC损伤的影响及其可能的分子机制。白藜芦醇可抑制LDL氧化为oxLDL。此外，oxLDL引起的氧化应激和细胞损伤被白藜芦醇减弱。暴露于oxLDL的CEC诱导细胞收缩，DNA片段化和细胞凋亡，但白藜芦醇抵御这种损伤。应用Lox-1小干扰（si）RNA进入CEC减少了这种膜受体的翻译，同时增加了白藜芦醇对oxLDL诱导的细胞凋亡的保护。相比之下，Lox-1的过表达减弱了白藜芦醇的保护作用。白藜芦醇抑制oxLDL诱导的Lox-1 mRNA和蛋白表达。白藜芦醇和Lox-1 siRNA均降低oxLDL增强的促凋亡Bcl-2相关X蛋白（Bax）从细胞质向线粒体的转运。随后，oxLDL诱导的线粒体膜电位、细胞色素c释放和半胱天冬酶-9、-3和-6活性的改变被白藜芦醇降低。用Z-VEID-FMK（苄氧基羰基-Leu-Glu-His-Asp-氟甲基酮）预处理协同促进白藜芦醇对DNA断裂和细胞凋亡的保护。因此，本研究表明，白藜芦醇可以通过下调Lox-1介导的线粒体-细胞色素c-caspase蛋白酶途径的激活来保护CEC免受oxLDL诱导的凋亡损伤。Journal of Cerebral Blood Flow & Metabolism（2011）31，842-854; doi：10.1038/jcbfm.2010.180; 2010年10月13日在线发表
Cerebrovascular endothelial cells (CECs) are crucial components of the blood-brain barrier. Our previous study showed that oxidized low-density lipoprotein (oxLDL) induces apoptosis of CECs. This study was designed to further evaluate the effects of resveratrol on oxLDL-induced CEC insults and its possible molecular mechanisms. Resveratrol decreased the oxidation of LDL into oxLDL. Additionally, the oxLDL-caused oxidative stress and cell damage were attenuated by resveratrol. Exposure of CECs to oxLDL induced cell shrinkage, DNA fragmentation, and cell apoptosis, but resveratrol defended against such injuries. Application of Lox-1 small interference (si) RNA into CECs reduced the translation of this membrane receptor, and simultaneously increased resveratrol protection from oxLDL-induced cell apoptosis. By comparison, overexpression of Lox-1 attenuated resveratrol protection. Resveratrol inhibited oxLDL-induced Lox-1 mRNA and protein expressions. Both resveratrol and Lox-1 siRNA decreased oxLDL-enhanced translocation of proapoptotic Bcl-2-associated X protein (Bax) from the cytoplasm to mitochondria. Sequentially, oxLDL-induced alterations in the mitochondrial membrane potential, cytochrome c release, and activities of caspases-9, -3, and -6 were decreased by resveratrol. Pretreatment with Z-VEID-FMK (benzyloxy-carbonyl-Leu-Glu-His-Asp-fluoromethyl ketone) synergistically promoted resveratrol's protection against DNA fragmentation and cell apoptosis. Therefore, this study shows that resveratrol can protect CECs from oxLDL-induced apoptotic insults via downregulating Lox-1-mediated activation of the Bax-mitochondria-cytochrome c-caspase protease pathway. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 842-854; doi:10.1038/jcbfm.2010.180; published online 13 October 2010