Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCζ-dependent manner in vascular smooth muscle cells.
Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCζ-dependent manner in vascular smooth muscle cells.
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DOI：
10.2337/db11-0990
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发表时间：
2012-01
期刊：
影响因子：
7.7
通讯作者：
Clemmons DR
中科院分区：
文献类型：
--
作者：
Xi G;Shen X;Maile LA;Wai C;Gollahon K;Clemmons DR
高血糖期间IGF-1刺激的肉瘤病毒癌基因（Src）激活是传播下游信号所必需的。本研究的目的是确定高血糖增强IGF-I刺激的Src激活的机制，以及NADPH氧化酶4（Nox 4）和蛋白激酶C β（PKC β）在介导血管平滑肌细胞（VSMC）的这种反应中的作用。在暴露于高血糖的VSMCs中分析Nox 4表达。通过敲低Nox 4，研究了Nox 4衍生的活性氧（ROS）在IGF-I刺激的Src活化中的作用。不同亚型的PKC进行了筛选，以探讨其在高血糖诱导的Nox 4。Src的氧化被证明是在高血糖期间响应IGF-I而激活Src的先决条件。高血压诱导Nox 4，但不是Nox 1，和p22吞噬细胞氧化酶（p22 phox）的表达和IGF-I刺激Nox 4/p22 phox复合物的形成，导致增加ROS的产生。敲低Nox 4阻止ROS的产生，并损害Src的氧化和激活响应IGF-I，而敲低Nox 1没有影响。PKC β介导高血糖诱导的Nox 4表达增加。在糖尿病小鼠中证实了培养的VSMC中的关键观察结果。Nox 4衍生的ROS负责高血糖对IGF-I刺激的Src活化的增强作用，这反过来又放大了IGF-I相关的下游信号传导和生物学作用。
IGF-I–stimulated sarcoma viral oncogene (Src) activation during hyperglycemia is required for propagating downstream signaling. The aim of the current study was to determine the mechanism by which hyperglycemia enhances IGF-I–stimulated Src activation and the role of NADPH oxidase 4 (Nox4) and protein kinase C ζ (PKCζ) in mediating this response in vascular smooth muscle cells (VSMCs). Nox4 expression was analyzed in VSMCs exposed to hyperglycemia. The role of Nox4-derived reactive oxygen species (ROS) in IGF-I–stimulated Src activation was investigated via knockdown of Nox4. Different isoforms of PKC were screened to investigate their role in hyperglycemia-induced Nox4. The oxidation of Src was shown to be a prerequisite for its activation in response to IGF-I during hyperglycemia. Hyperglycemia induced Nox4, but not Nox1, and p22 phagocyte oxidase (p22phox) expression and IGF-I stimulated Nox4/p22phox complex formation, leading to increased ROS generation. Knockdown of Nox4 prevented ROS generation and impaired the oxidation and activation of Src in response to IGF-I, whereas knockdown of Nox1 had no effect. PKCζ was shown to mediate the hyperglycemia-induced increase in Nox4 expression. The key observations in cultured VSMCs were confirmed in the diabetic mice. Nox4-derived ROS is responsible for the enhancing effect of hyperglycemia on IGF-I–stimulated Src activation, which in turn amplifies IGF-I–linked downstream signaling and biological actions.
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影响因子：
3.4
作者：
Grandis, M;Nobbio, L;Schenone, A
通讯作者：
Schenone, A
影响因子：
4.8
作者：
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影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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