De Geest Bart, Mishra Mudit
Centre for Molecular and Vascular Biology, Catholic University of Leuven, 3000 Leuven, Belgium.
Department of Cardiothoracic Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Biomedicines. 2021 Nov 9;9(11):1645. doi: 10.3390/biomedicines9111645.
Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure.
在生理情况下，活性氧（ROS）的产生与降解之间存在着精确的平衡，导致稳态ROS水平较低。ROS参与正常的细胞功能和细胞内稳态。氧化应激是稳态ROS水平短暂或持续升高的状态，会导致信号通路紊乱和细胞成分的氧化修饰。它是病理性肥大、病理性重塑以及心力衰竭发生和发展过程中的关键病理生理因素。心脏是代谢最活跃的器官，其线粒体含量在所有组织中最高。线粒体是心肌中ROS的主要来源。对三种主要抗氧化酶、硫氧还蛋白和血红素加氧酶-1进行基因转移研究，突出了氧化应激在心力衰竭中的因果作用，针对纠正与代谢危险因素相关的氧化应激的基因治疗研究进一步支持了这一作用。此外，基因转移研究表明，氧化还原敏感的微小RNA构成了治疗心力衰竭的潜在治疗靶点。总之，基因治疗研究为氧化应激在病理性重塑和心力衰竭发展中的关键作用提供了有力的确证。
