p66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke.
p66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke.
复制标题
p66Shc 介导依赖于香烟烟雾诱导的气道上皮细胞 PKC 激活的线粒体功能障碍
DOI：
10.1155/2018/5837123
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发表时间：
2018
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Zhang M;Tang J;Shan H;Zhang Q;Yang X;Zhang J;Li Y
气道上皮线粒体损伤在慢性阻塞性肺疾病（COPD）的发病机制中起关键作用。p66Shc接头蛋白是一种新发现的线粒体功能障碍介质。然而，对于p66Shc在COPD发展过程中对气道上皮损伤的影响知之甚少。本研究的目的是探讨p66Shc及其上游调节因子在香烟烟雾提取物（CSE）诱导的气道上皮细胞线粒体损伤（Beas-2b）中的作用。本研究发现，CSE以浓度依赖性和时间依赖性的方式增加了气道上皮细胞p66Shc的表达及其线粒体易位。当7.5% CSE刺激气道上皮细胞时，p66Shc siRNA显著减轻了线粒体功能障碍和细胞损伤。当气道上皮细胞暴露于7.5% CSE时，PKCβ和PKCδ的总表达和磷酸化表达显著增加，与线粒体功能障碍和细胞损伤相关。在7.5% CSE培养的气道上皮细胞中，药理抑制剂PKCβ和PKCδ可显著抑制p66Shc磷酸化及其线粒体易位，保护线粒体和细胞免受氧化损伤。这些数据表明，新的PKCβ/δ-p66Shc信号通路可能参与COPD和其他氧化应激相关肺部疾病的发病机制，并为这些疾病提供潜在的治疗靶点。
Airway epithelial mitochondrial injury plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction. However, little is known about the effect of p66Shc on airway epithelial damage in the development of COPD. The aim of the present study is to investigate the roles of p66Shc and its upstream regulators in the mitochondrial injury of airway epithelial cells (Beas-2b) induced by cigarette smoke extract (CSE). Our present study revealed that CSE increased p66Shc expression and its mitochondrial translocation in concentration and time-dependent manners in airway epithelial cells. And p66Shc siRNA significantly attenuated mitochondrial dysfunction and cell injury when airway epithelial cells were stimulated with 7.5% CSE. The total and phosphorylated expression of PKCβ and PKCδ was significantly increased associated with mitochondrial dysfunction and cell injury when airway epithelial cells were exposed to 7.5% CSE. The pretreatments with pharmacological inhibitors of PKCβ and PKCδ could notably suppress p66Shc phosphorylation and its mitochondrial translocation and protect the mitochondria and cells against oxidative damage when airway epithelial cells were incubated with 7.5% CSE. These data suggest that a novel PKCβ/δ-p66Shc signaling pathway may be involved in the pathogenesis of COPD and other oxidative stress-associated pulmonary diseases and provide a potential therapeutic target for these diseases.
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影响因子：
3.1
作者：
Ragupathy S;Esmaeili F;Paschoud S;Sublet E;Citi S;Borchard G
通讯作者：
Borchard G
影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
12.4
作者：
Denning, MF;Wang, Y;Qin, JZ
通讯作者：
Qin, JZ
影响因子：
4.6
作者：
Khalid S;Drasche A;Thurner M;Hermann M;Ashraf MI;Fresser F;Baier G;Kremser L;Lindner H;Troppmair J
通讯作者：
Troppmair J
影响因子：
56.9
作者：
Pinton, Paolo;Rimessi, Alessandro;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario