Selemidis Stavros, Sobey Christopher G, Wingler Kirstin, Schmidt Harald H H W, Drummond Grant R
Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Pharmacol Ther. 2008 Dec;120(3):254-91. doi: 10.1016/j.pharmthera.2008.08.005. Epub 2008 Aug 28.
Until the 1970s, reactive oxygen species (ROS) were considered merely harmful by-products of aerobic respiration and the driving force behind the evolution of an array of cellular antioxidant enzymes with the purpose of rapidly metabolising ROS to minimise their oxidising effects. However, the perception that ROS are only harmful to cells has since been questioned by a burgeoning body of evidence pointing to the existence of enzymes with the dedicated function of generating ROS. NADPH oxidases represent the only known family of enzymes whose sole purpose is to generate ROS. Members of this enzyme family are expressed across mammalian and non-mammalian cells, and influence a multitude of biological functions including host defence and redox signalling. However, although ROS are deliberately generated by NADPH oxidases during normal cell physiology, the observations that their expression and activity is markedly upregulated in the blood vessel wall in a number of cardiovascular 'high-risk' states (e.g. hypertension, hypercholesterolemia) implicates them in the oxidative stress that gives rise to artery disease and ultimately heart attacks and strokes. These observations highlight the fact that NADPH oxidases are important therapeutic targets in cardiovascular disease and that, hence, there is clearly a need for the development of selective inhibitors of these enzymes. Here we highlight the structural and biochemical characteristics of the NADPH oxidase family and then comprehensively review the literature on the currently available pharmacological inhibitors of these enzymes with a particular emphasis on their mechanisms of action, isoform selectivity and therapeutic potential in cardiovascular disease.
直到20世纪70年代，活性氧（ROS）仅仅被视为有氧呼吸的有害副产物，以及一系列细胞抗氧化酶进化背后的驱动力，这些抗氧化酶的目的是快速代谢ROS以将其氧化作用降至最低。然而，自那时起，越来越多的证据表明存在具有专门产生ROS功能的酶，这使得ROS仅对细胞有害这一观念受到了质疑。NADPH氧化酶是唯一已知的一类其唯一目的就是产生ROS的酶。该酶家族的成员在哺乳动物和非哺乳动物细胞中均有表达，并影响包括宿主防御和氧化还原信号传导在内的多种生物学功能。然而，尽管在正常细胞生理过程中NADPH氧化酶会有意地产生ROS，但在一些心血管“高危”状态（如高血压、高胆固醇血症）下，其在血管壁中的表达和活性会显著上调，这表明它们与导致动脉疾病以及最终引发心脏病发作和中风的氧化应激有关。这些观察结果突出了一个事实，即NADPH氧化酶是心血管疾病重要的治疗靶点，因此显然需要开发这些酶的选择性抑制剂。在此，我们将重点介绍NADPH氧化酶家族的结构和生化特性，然后全面综述有关这些酶目前可用的药理抑制剂的文献，特别强调它们的作用机制、同工型选择性以及在心血管疾病中的治疗潜力。
