Ginkgo biloba extract confers protection from cigarette smoke extract-induced apoptosis in human lung endothelial cells: Role of heme oxygenase-1
Ginkgo biloba extract confers protection from cigarette smoke extract-induced apoptosis in human lung endothelial cells: Role of heme oxygenase-1
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DOI：
10.1016/j.pupt.2009.02.003
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发表时间：
2009-08-01
影响因子：
3.2
通讯作者：
Kou, Yu Ru
中科院分区：
文献类型：
--
作者：
Hsu, Chiu-Ling;Wu, Yuh-Lin;Kou, Yu Ru
吸烟是慢性阻塞性肺疾病的主要原因，这与肺中氧化应激和凋亡内皮细胞数量增加有关。银杏叶提取物（EGb）是用于诸如血管功能不全和阿尔茨海默病的疾病的治疗剂。虽然银杏叶提取物具有抗氧化功能，但其减轻香烟烟雾引起的病理生理后果的能力尚未阐明。我们研究了EGb对香烟烟雾提取物（CSE）诱导的人肺动脉内皮细胞（HPAECs）氧化应激和凋亡的保护作用及其机制。用CSE（160 μ g/ml）激发引起HPAEC细胞活力降低、细胞内活性氧增加和半胱天冬酶依赖性凋亡加速，所有这些都可通过EGb（100 μ g/ml）预处理减轻。N-乙酰半胱氨酸（一种抗氧化剂）也减少了CSE诱导的氧化应激和细胞凋亡，表明前者的反应优于后者。此外，EGb激活ERK、JNK和p38 [三种主要的促分裂原活化蛋白激酶（MAPK）]，增加核因子红细胞2相关因子2（Nrf 2）的核水平，上调血红素加氧酶-1（HO-1，一种具有抗氧化功能的应激反应蛋白）。MAPKs抑制剂的预处理废除EGb诱导的Nrf 2核转位和HO-1上调。针对HO-1的小干扰RNA阻止了EGb诱导的HO-1上调，并且也废除了EGb在CSE损伤的HPAEC中的抗氧化、抗凋亡和细胞保护作用。我们的结论是，EGb赋予保护氧化应激相关的细胞凋亡诱导的CSE HPAECs和其治疗效果依赖于HO-1的转录上调EGb通过MAPKs/Nrf 2通路。(C)2009爱思唯尔有限公司版权所有。
Cigarette smoking is the major cause of chronic obstructive pulmonary disease, which is associated with increased oxidative stress and numbers of apoptotic endothelial cells in the lungs. Ginkgo biloba extract (EGb) is a therapeutic agent for disorders such as vascular insufficiency and Alzheimer's disease. Although EGb is known to possess antioxidant functions, its ability to alleviate cigarette smoke-induced pathophysiological consequences has not been elucidated. We investigated the cytoprotective effects and therapeutic mechanisms of EGb against oxidative stress and apoptosis induced by cigarette smoke extract (CSE) in human pulmonary artery endothelial cells (HPAECs). Challenge with CSE (160 mu g/ml) caused a reduction in cell viability, an increase in intracellular reactive oxygen species and an acceleration of caspase-dependant apoptosis in HPAECs, all of which were alleviated by pretreatment with EGb (100 mu g/ml). N-acetylcysteine (an antioxidant) also reduced both the CSE-induced oxidative stress and apoptosis, indicating that the former response trigged the latter. Additionally, EGb produced activation of ERK, JNK and p38 [three major mitogen-activated protein kinases (MAPKs)], an increase in the nuclear level of nuclear factor erythroid-2-related factor 2 (Nrf2) and upregulation of heme oxygenase-1 (HO-1, a stress-responsive protein with antioxidant function). Pretreatment with inhibitors of MAPKs abolished both EGb-induced Nrf2 nuclear translocation and HO-1 upregulation. Small interfering RNAs targeting HO-1 prevented EGb-induced HO-1 upregulation and also abolished the antioxidant, anti-apoptotic and cytoprotective effects of EGb in HPAECs insulted with CSE. We conclude that EGb confers protection from oxidative stress-related apoptosis induced by CSE in HPAECs and its therapeutic effects depend on transcriptional upregulation of HO-1 by EGb via the MAPKs/Nrf2 pathway. (C) 2009 Elsevier Ltd. All rights reserved.