Department of Vascular and Thoracic Surgery, University of Antwerp, Antwerp, Belgium.
Free Radic Biol Med. 2011 Apr 1;50(7):765-76. doi: 10.1016/j.freeradbiomed.2010.12.018. Epub 2010 Dec 21.
The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.
同二聚体黄素蛋白内皮型一氧化氮合酶（eNOS）将 l-精氨酸氧化为 l-瓜氨酸和一氧化氮（NO），从而使血管急性扩张并抑制血小板聚集。从长远来看，eNOS 通过减少白细胞黏附和平滑肌增殖，在调节血压和预防动脉粥样硬化方面发挥主要作用。然而，血管氧化还原平衡的紊乱会导致 eNOS 损伤和氧激活与 l-精氨酸转化的解偶联。解偶联的 eNOS 单体化并产生活性氧（ROS）而不是 NO。事实上，eNOS 解偶联被认为是广泛的心血管和肺部疾病（如动脉粥样硬化、心室重构和肺动脉高压）的主要发病机制之一。因此，调节解偶联的 eNOS，特别是依赖于 eNOS 的 ROS 生成，是预防和/或治疗心肺疾病的一种有吸引力的治疗方法，包括心胸外科手术期间的保护作用。这篇综述全面概述了解偶联的 eNOS 在心血管和肺部疾病中的致病作用。此外，还详细讨论了相关的治疗可能性，如补充 eNOS 底物 l-精氨酸、挥发性一氧化氮和直接一氧化氮供体以及 eNOS 调节剂，如 eNOS 辅助因子四氢生物蝶呤和叶酸。
