Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence, London, UK.
Antioxid Redox Signal. 2013 Mar 20;18(9):1024-41. doi: 10.1089/ars.2012.4550. Epub 2012 Aug 27.
Oxidative stress is involved in the pathogenesis of heart failure but clinical antioxidant trials have been unsuccessful. This may be because effects of reactive oxygen species (ROS) depend upon their source, location, and concentration. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) proteins generate ROS in a highly regulated fashion and modulate several components of the heart failure phenotype.
Two Nox isoforms, Nox2 and Nox4, are expressed in the heart. Studies using gene-modified mice deficient in Nox2 activity indicate that Nox2 activation contributes to angiotensin II-induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis but may also positively modulate physiological excitation-contraction coupling. Nox2 contributes to myocyte death under stress situations and plays important roles in postmyocardial infarction remodeling, in part by modulating matrix metalloprotease activity. In contrast to Nox2, Nox4 is constitutively active at a low level and induces protective effects in the heart under chronic stress, for example, by maintaining myocardial capillary density. However, high levels of Nox4 could have detrimental effects.
The effects of Nox proteins during the development of heart failure likely depend upon the isoform, activation level, and cellular distribution, and may include beneficial as well as detrimental effects. More needs to be learnt about the precise regulation of abundance and biochemical activity of these proteins in the heart as well as the downstream signaling pathways that they regulate.
The development of specific approaches to target individual Nox isoforms and/or specific cell types may be important for the achievement of therapeutic efficacy in heart failure.
氧化应激与心力衰竭的发病机制有关，但临床抗氧化试验均未成功。这可能是因为活性氧（ROS）的作用取决于其来源、位置和浓度。烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox）蛋白以高度调控的方式产生 ROS，并调节心力衰竭表型的几个组成部分。
两种 Nox 同工型，Nox2 和 Nox4，在心脏中表达。使用基因修饰的 Nox2 活性缺乏的小鼠研究表明，Nox2 激活有助于血管紧张素 II 诱导的心肌细胞肥大、心房颤动和间质纤维化的发展，但也可能积极调节生理兴奋-收缩偶联。Nox2 在应激情况下有助于心肌细胞死亡，并在心肌梗死后重塑中发挥重要作用，部分是通过调节基质金属蛋白酶活性。与 Nox2 相反，Nox4 以低水平组成性激活，并在慢性应激下对心脏产生保护作用，例如通过维持心肌毛细血管密度。然而，高水平的 Nox4 可能有不利影响。
Nox 蛋白在心力衰竭发展过程中的作用可能取决于同工型、激活水平和细胞分布，并可能包括有益和有害的影响。需要更多地了解这些蛋白质在心脏中的丰度和生化活性的精确调节以及它们调节的下游信号通路。
针对特定 Nox 同工型和/或特定细胞类型的特定方法的开发可能对心力衰竭的治疗效果很重要。
