Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells
Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells
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DOI：
10.1016/j.cardiores.2005.04.017
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发表时间：
2005-09-01
影响因子：
10.8
通讯作者：
Kurabayashi, M
中科院分区：
文献类型：
--
作者：
Sato, H;Sato, M;Kurabayashi, M
目的：动脉粥样硬化斑块增厚时，由于血流灌注不良，易出现缺氧。在这项研究中，我们测试了（a）活性氧（ROS）和c-Src是否在兔主动脉平滑肌细胞系C2/2细胞和大鼠主动脉平滑肌细胞原代培养物中缺氧诱导HIF-1 α蛋白和派-1基因表达中发挥作用，以及（B）线粒体如何作用于缺氧诱导的信号传导机制。低氧暴露增加C2/2细胞H2 O2生成、c-Src磷酸化、HIF-1 α蛋白表达和派-1基因表达。过氧化氢酶作为H2 O2的清除剂，可抑制低氧诱导的ROS产生和派-1基因表达。Src激酶抑制剂PP 1和PP 2抑制缺氧诱导的HIF-1 α蛋白和派-1基因表达。鱼藤酮对缺氧诱导的线粒体呼吸作用的抑制作用主要表现在缺氧诱导的ROS产生、c-Src磷酸化、HIF-1 α蛋白表达和派-1基因表达。结论：缺氧诱导的血管平滑肌细胞HIF-1 α蛋白和派-1基因表达受ROS产生和c-Src激活的调节。线粒体将缺氧信号与c-Src连接，这反过来导致HIF-1 α蛋白和派-1基因表达。这些结果提供了证据，缺氧诱导ROS介导的和c-Src依赖的信号级联反应，这是密切相关的血管生成和血栓形成在动脉粥样硬化血管。(c)2005年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1 alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism.Methods and results: Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1 alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1 alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1 alpha protein expression, and PAI-1 gene expression.Conclusion: Induction of HIF-1 alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1 alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.