Department of Pharmacology, Cardiovascular Research Institute Maastricht, Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University, The Netherlands.
Cell Mol Life Sci. 2012 Jul;69(14):2327-43. doi: 10.1007/s00018-012-1010-9. Epub 2012 May 31.
Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.
活性氧 (ROS) 既是细胞信号分子，也是疾病触发因素；与还原当量相比，其相对过剩（氧化应激）或不足（还原应激）可能具有危害性。这也许可以解释为什么抗氧化剂无法对抗与氧化应激相关的疾病。相反，针对与疾病相关的、能产生 ROS 的酶促 ROS 源，而不影响生理 ROS 信号可能更有益。NADPH 氧化酶是唯一已知具有产生 ROS 这一单一功能的酶家族。在催化 NADPH 氧化酶亚基 (NOX) 中，NOX4 是分布最广泛的同工型。本文批判性地回顾了目前可用于评估 NOX 尤其是 NOX4 作用的实验工具，即敲除小鼠、siRNA、抗体和药理学抑制剂。然后，我们重点介绍小分子 NADPH 氧化酶抑制剂 VAS2870 的体外和体内特性、特异性、选择性及其可能的作用机制。最后，我们讨论了将 NOX4 作为治疗靶点用于包括中风、心力衰竭和纤维化等适应症的验证。
