Li Jian-Mei, Shah Ajay M
Department of Cardiology, GKT School of Medicine, King's College of London, SE5 9PJ, UK.
Am J Physiol Regul Integr Comp Physiol. 2004 Nov;287(5):R1014-30. doi: 10.1152/ajpregu.00124.2004.
The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O2-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), nitric oxide (NO), and hydroxyl (OH) radicals. The O2- radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H2O2 and ONOO-. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities ("redox signaling"); and 3) oxidative damage. Multiple enzymes can generate O2-, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O2-* involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.
内皮细胞产生活性氧（ROS）在生理过程以及许多心血管疾病的发病机制中都很重要。内皮细胞产生的ROS包括超氧阴离子（O2-）、过氧化氢（H2O2）、过氧亚硝酸盐（ONOO-）、一氧化氮（NO）和羟自由基（OH）。超氧阴离子自由基（O2-）是本综述的重点，它可能直接产生多种效应，也可能通过生成其他自由基，如H2O2和ONOO-来发挥作用。这些效应包括：1）使强效信号分子和内皮源性舒张因子NO迅速失活，导致内皮功能障碍；2）介导信号转导，导致基因转录以及蛋白质和酶活性改变（“氧化还原信号传导”）；3）氧化损伤。多种酶可产生O2-，尤其是黄嘌呤氧化酶、解偶联型一氧化氮合酶和线粒体。最近的研究表明，参与氧化还原信号传导的内皮O2-*的主要来源是一种多组分吞噬细胞型NADPH氧化酶，它受到诸如振荡切应力、缺氧、血管紧张素II、生长因子、细胞因子和高脂血症等刺激的特定调节。根据产生的氧化剂水平以及促氧化和抗氧化途径之间的相对平衡，ROS可能参与细胞生长、肥大、凋亡、内皮激活和黏附，例如在糖尿病、高血压、动脉粥样硬化、心力衰竭和缺血再灌注中。本文综述了我们目前关于内皮ROS产生的来源、其调节、其参与氧化还原信号传导以及增强的ROS产生和氧化还原信号传导与涉及内皮激活和功能障碍的心血管疾病病理生理学相关性的知识。
