NADPH oxidase 4 is required for interleukin-1β-mediated activation of protein kinase Cδ and downstream activation of c-jun N-terminal kinase signaling in smooth muscle.
NADPH oxidase 4 is required for interleukin-1β-mediated activation of protein kinase Cδ and downstream activation of c-jun N-terminal kinase signaling in smooth muscle.
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DOI：
10.1016/j.freeradbiomed.2012.09.026
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发表时间：
2013-01
影响因子：
7.4
通讯作者：
Jourd'heuil, David
中科院分区：
文献类型：
--
作者：
Ginnan, Roman;Jourd'heuil, Frances L.;Guikema, Benjamin;Simons, Malorie;Singer, Harold A.;Jourd'heuil, David
关键词：
活性氧（ROS）是在促炎细胞因子刺激下在血管壁中产生的，并且是由于血管损伤而发生的多种细胞反应的重要介质。NADPH氧化酶（NOX）蛋白家族成员已被确定为血管平滑肌细胞（VSM）中ROS的重要来源。在这项研究中，我们测试了这样的假设：NOX 4是IL-1β依赖性PKCδ激活的近端介质，并增加原代大鼠主动脉VSM细胞中IL-1β刺激的c-Jun激酶（JNK）信号传导。我们发现用IL-1β刺激VSM细胞可增加PKCδ活性和细胞内ROS的产生。SiRNA沉默NOX 4而非NOX 1消除了ROS产生中的IL-1β依赖性增加。PKCδ活性的药理学抑制以及PKCδ或NOX 4的siRNA消耗阻断了JNK的IL-1β依赖性活化。进一步的研究表明，IL-1β依赖的iNOS表达上调通过JNK抑制和NOX 4沉默而被抑制。综上所述，这些结果表明，IL-1β依赖性的PKCδ活化受NOX 4衍生的ROS调节。我们的研究定位PKCδ作为一个重要的氧化还原敏感介导的IL-1β依赖性信号和下游激活的炎症介质在VSM细胞。
Reactive oxygen species (ROS) are generated in the vascular wall upon stimulation by pro-inflammatory cytokines and are important mediators of diverse cellular responses that occur as a result of vascular injury. Member of the NADPH oxidase (NOX) family of proteins have been identified in vascular smooth muscle cells (VSM) as important sources of ROS. In this study, we tested the hypothesis that NOX4 is a proximal mediator of IL-1β-dependent activation of PKCδ and increases IL-1β stimulated c-Jun kinase (JNK) signaling in primary rat aortic VSM cells. We found that stimulation of VSM cells with IL-1β increased PKCδ activity and intracellular ROS generation. SiRNA silencing of NOX4 but not NOX1 ablated the IL-1β-dependent increase in ROS production. Pharmacological inhibition of PKCδ activity as well as siRNA depletion of PKCδ or NOX4 blocked the IL-1β-dependent activation of JNK. Further studies showed that the IL-1β-dependent upregulation of iNOS expression was inhibited through JNK inhibition and NOX4 silencing. Taken together, these results indicate that IL-1β-dependent activation of PKCδ is modulated by NOX4-derived ROS. Our study positions PKCδ as an important redox sensitive mediator of IL-1β-dependent signaling and downstream activation of inflammatory mediators in VSM cells.
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影响因子：
8.7
作者：
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通讯作者：
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影响因子：
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影响因子：
20.1
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DOI：
10.1161/atvbaha.108.164277
发表时间：
2008-07-01
影响因子：
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作者：
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通讯作者：
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DOI：
10.1161/atvbaha.107.150250
发表时间：
2008-01-01
影响因子：
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作者：
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通讯作者：
Jiang, Bingbing