Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract
Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract
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DOI：
10.1016/j.atherosclerosis.2010.11.010
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发表时间：
2011-02-01
期刊：
影响因子：
5.3
通讯作者：
Chen, Jaw-Wen
中科院分区：
文献类型：
--
作者：
Chen, Jia-Shiong;Huang, Po-Hsun;Chen, Jaw-Wen
目的：银杏叶提取物(GBE)的血管保护作用可能同时涉及抗氧化和抗炎机制。银杏叶提取物最近被认为是一种血红素加氧酶-1的诱导剂。HO-1在银杏叶提取物抗动脉粥样硬化及相关血管保护作用中的作用有待进一步阐明。方法与结果：用肿瘤坏死因子-α刺激人主动脉内皮细胞与单核细胞的黏附，这是一种模拟动脉粥样硬化形成的体外信号。银杏叶提取物可降低肿瘤坏死因子-α刺激的内皮细胞黏附性，这种作用可被HO-1抑制剂ZnPP IX或SnPP IX减弱。银杏叶提取物可增加HAECs HO-1的表达和酶活性。MAP激酶抑制剂SB203580可显著降低GBE诱导的HO-1表达。此外，银杏叶提取物激活了转录因子核因子-红系2相关因子2(Nrf2)的易位，并增加了其与HO-1基因的抗氧化反应元件(ARE)的结合。用聚乙二醇超氧化物歧化酶或其他抗氧化剂预处理并不改变GBE诱导的内皮细胞HO-1的表达。体内实验还表明，银杏叶提取物可减少白细胞与损伤动脉的黏附，增强循环单核细胞和钢丝损伤后动脉中HO-1的表达，提示银杏叶提取物可在体内诱导HO-1的表达。结论：银杏叶提取物可通过激活p38和NRF-2途径诱导HO-1的表达，从而抑制细胞因子诱导的内皮黏附，其机制与氧化应激无直接关系。银杏叶提取物可能通过诱导血管HO-1表达发挥抗动脉粥样硬化和血管保护作用。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
Aims: Vascular protective effects of Ginkgo biloba extract (GBE) may involve both antioxidant-related and anti-inflammatory mechanisms. GBE was recently suggested as a heme oxygenase (HO)-1 inducer. The role of HO-1 in anti-atherogenesis and related vascular protective effects of GBE awaited further clarification.Methods and results: Tumor necrosis factor (TNF)-alpha was used to stimulate adhesiveness of human aortic endothelial cells (HAECs) to monocytes, an in vitro sign simulating atherogenesis. Pretreatment with GBE reduced TNF-alpha-stimulated endothelial adhesiveness, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. GBE increased HO-1 expression and enzyme activity in HAECs. Pretreatment with MAP kinase inhibitor SB203580 significantly reduced GBE-induced HO-1 expression. Furthermore, GBE activated the translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increased its binding to the antioxidant response element (ARE) of the HO-1 gene. Pretreatment with PEG-SOD or other antioxidant reagents did not alter GBE-induced endothelial HO-1 expression. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injury arteries, and enhance HO-1 expression in circulating monocytes and in arteries after wire injury, suggesting the in vivo induction of HO-1 by GBE.Conclusion: GBE could inhibit cytokine-induced endothelial adhesiveness by inducing HO-1 expression via the activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression. (C) 2010 Elsevier Ireland Ltd. All rights reserved.