Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species.
Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species.
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DOI：
10.1016/j.freeradbiomed.2014.04.029
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发表时间：
2014-08
影响因子：
7.4
通讯作者：
Fulton, David J. R.
中科院分区：
文献类型：
--
作者：
Chen, Feng;Barman, Scott;Yu, Yanfang;Haigh, Steven;Wang, Yusi;Dou, Huijuan;Bagi, Zsolt;Han, Weihong;Su, Yunchao;Fulton, David J. R.
小窝蛋白 -1（Cav -1）表达和功能的改变被认为是许多心血管疾病的潜在致病机制。Cav -1通过其支架结构域与众多信号蛋白相互作用，结合并调节它们的活性。在内皮细胞中，Cav -1已被证明可减少活性氧（ROS）的产生，但Cav -1是否调节细胞内ROS的主要来源——NADPH氧化酶（Nox）的活性尚未得到证实。在此，我们发现Cav -1主要在肺动脉（PA）的内皮和外膜中表达，并且在多种肺动脉高压（PH）模型的分离肺动脉中Cav -1表达降低。Cav -1表达降低与高血压肺动脉外膜中ROS产生增加相关。体外实验表明，Cav -1及其支架结构域具有显著抑制Nox1 - 5活性的能力，还发现Cav -1与Nox5和Nox2结合，但不与Nox4结合。除了翻译后作用外，在原代细胞中，Cav -1通过抑制NF - κB通路抑制Nox2和Nox4的mRNA和蛋白质表达。最后，在小鼠缺氧模型中，Cav -1基因敲除增加了Nox2和Nox4的表达，并加剧了肺动脉高压。总之，这些结果表明，Cav -1通过两种不同的机制对Nox功能起负调节作用，即急性通过直接结合，慢性通过改变表达水平。因此，在心血管疾病（如肺动脉高压）中Cav -1表达的缺失可能是Nox活性增加和ROS产生增多的原因。
Changes in the expression and function of caveolin-1 (Cav-1) have been proposed as a pathogenic mechanism underlying many cardiovascular diseases. Cav-1 binds to and regulates the activity of numerous signaling proteins via interactions with its scaffolding domain. In endothelial cells, Cav-1 has been shown to reduce reactive oxygen species (ROS) production, but whether Cav-1 regulates the activity of NADPH oxidases (Nox), a major source of cellular ROS, has not yet been shown. Herein, we show that Cav-1 is primarily expressed in the endothelium and adventitia of pulmonary arteries (PA) and that Cav-1 expression is reduced in isolated PA from multiple models of pulmonary artery hypertension (PH). Reduced Cav-1 expression correlates with increased ROS production in the adventitia of hypertensive PA. In vitro experiments revealed a significant ability of Cav-1 and its scaffolding domain to inhibit Nox1-5 activity and it was also found that Cav-1 binds to Nox5 and Nox2 but not Nox4. In additional to post-translational actions, in primary cells, Cav-1 represses the mRNA and protein expression of Nox2 and Nox4 though inhibition of the NF-kB pathway. Lastly, in a mouse hypoxia model, the genetic ablation of Cav-1 increased the expression of Nox2 and Nox4 and exacerbated PH. Together, these results suggest that Cav-1 is a negative regulator of Nox function via two distinct mechanisms, acutely through direct binding and chronically through alteration of expression levels. Accordingly, the loss of Cav-1 expression in cardiovascular diseases such as PH may account for the increased Nox activity and greater production of ROS.
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影响因子：
4.4
作者：
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通讯作者：
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