Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China.
J Thromb Haemost. 2010 Feb;8(2):397-406. doi: 10.1111/j.1538-7836.2009.03683.x. Epub 2009 Nov 6.
CD40 ligand (CD40L) has been implicated as an inducer of reactive oxygen species (ROS) generation in endothelial cells, but definitive evidence for this and the in vivo relevance haves not been demonstrated fully. We thus investigated whether phosphoinositide 3-kinase (PI3K) was linked to ROS generation and endothelial reactivity in response to CD40L.
CD40L treatment activated PI3K activity by regulating the association between PI3K p85 and the CD40 receptor. CD40L exposure also stimulated the GTPase Rac1, which is known to activate NADPH oxidases, and enhanced ROS formation, whereas PI3K inhibition or depletion by small interfering RNA (siRNA) prevented these responses. Subsequently, PI3K overexpression activated Rac1 and increased ROS generation. These responses were not observed in the presence of inactive Rac1 or siRNA against the NADPH oxidase subunit NOX2. Protein kinase Czeta mediates PI3K-regulated NADPH oxidase activation by promoting cellular p47phox translocation. Importantly, PI3K inhibition prevented CD40L-mediated ROS generation and endothelial dysfunction in a mouse model. In summary, PI3K mediates CD40L-induced ROS production and subsequent endothelial dysfunction.
Targeting PI3K may provide a new therapeutic approach in diseases associated with oxidative stress and endothelial dysfunction.
CD40 配体（CD40L）已被认为是内皮细胞中活性氧（ROS）生成的诱导剂，但尚未充分证明其在体内的相关性和确切证据。因此，我们研究了 PI3K 是否与 CD40L 诱导的 ROS 生成和内皮反应有关。
CD40L 通过调节 PI3K p85 与 CD40 受体之间的关联来激活 PI3K 活性。CD40L 暴露还刺激了已知能激活 NADPH 氧化酶的 GTPase Rac1，并增强了 ROS 的形成，而 PI3K 抑制或通过小干扰 RNA（siRNA）耗竭则阻止了这些反应。随后，PI3K 过表达激活 Rac1 并增加 ROS 的生成。在存在无活性 Rac1 或针对 NADPH 氧化酶亚单位 NOX2 的 siRNA 的情况下，没有观察到这些反应。蛋白激酶 Czeta 通过促进细胞 p47phox 易位来介导 PI3K 调节的 NADPH 氧化酶的激活。重要的是，PI3K 抑制可预防 CD40L 介导的 ROS 生成和内皮功能障碍在小鼠模型中。总之，PI3K 介导 CD40L 诱导的 ROS 产生和随后的内皮功能障碍。
靶向 PI3K 可能为与氧化应激和内皮功能障碍相关的疾病提供新的治疗方法。
