BHF Field Marshal Earl Alexander Professor of Cardiovascular Medicine, University of Oxford and Oxford University Hospitals, Oxford, UK.
Handb Exp Pharmacol. 2021;264:339-352. doi: 10.1007/164_2020_390.
Generation of nitric oxide (NO) by the nitric oxide synthase (NOS) enzymes plays multiple signalling roles in every organ system, with crucial roles in the cardiovascular system, mediated by endothelial nitric oxide synthase (eNOS, encoded by NOS3) and neuronal nitric oxide synthase (nNOS, encoded by NOS1) in regulation of blood pressure, flow, oxygen delivery and cardiac function. Loss of normal NO-mediated functions in cardiovascular disease state is associated with changes in nitroso-redox signalling that are not dependent solely upon altered NO generation, but increased generation of reactive oxygen species (ROS). The NOS enzymes can also generate ROS, in a catalytic mode whereby the generation of NO from L-arginine is 'uncoupled' from the reduction of molecular oxygen. NOS uncoupling is determined by several factors, including the availability and oxidation state of the required NOS cofactor, tetrahydrobiopterin (BH4). The duality of NOS functions as enzymes that generate both NO and ROS under different regulatory states has emerged as an important pathophysiologic mechanism, and is a potential therapeutic target, via agents that can maintain or restore NOS coupling, for example via effects on BH4 availability.
一氧化氮合酶（NOS）生成的一氧化氮（NO）在每个器官系统中发挥多种信号作用，在心血管系统中通过内皮型一氧化氮合酶（eNOS，由 NOS3 编码）和神经元型一氧化氮合酶（nNOS，由 NOS1 编码）介导血压、血流、氧气输送和心脏功能的调节中发挥关键作用。在心血管疾病状态下，正常的 NO 介导功能丧失与硝基氧化还原信号的变化有关，这些变化不仅取决于 NO 生成的改变，还与活性氧（ROS）的生成增加有关。NOS 酶也可以以催化方式生成 ROS，其中 L-精氨酸的 NO 生成与分子氧的还原“解偶联”。NOS 解偶联由几个因素决定，包括所需 NOS 辅助因子四氢生物蝶呤（BH4）的可用性和氧化状态。NOS 在不同调节状态下既能生成 NO 又能生成 ROS 的双重功能已成为一个重要的病理生理机制，通过维持或恢复 NOS 偶联的药物，例如通过影响 BH4 的可用性，成为一个潜在的治疗靶点。
