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INVITED REVIEW
Department of Cardiology, Guy's King's and St Thomas's School of Medicine, King's College London, London SE5 9PJ, United Kingdom
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.
antioxidant; NADPH oxidase; oxidative stress; reactive oxygen species; redox signaling
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