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Increased oxidative stress plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, and ischemia-reperfusion. Although several sources of reactive oxygen species (ROS) may be involved, a family of NADPH oxidases appears to be especially important for redox signaling and may be amenable to specific therapeutic targeting. These include the prototypic Nox2 isoform-based NADPH oxidase, which was first characterized in neutrophils, as well as other NADPH oxidases such as Nox1 and Nox4. These Nox isoforms are expressed in a cell- and tissue-specific fashion, are subject to independent activation and regulation, and may subserve distinct functions. This article reviews the potential roles of NADPH oxidases in both cardiovascular physiological processes (such as the regulation of vascular tone and oxygen sensing) and pathophysiological processes such as endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, angiogenesis, and vascular and cardiac remodeling. The complexity of regulation of NADPH oxidases in these conditions may provide the possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the disease process.

Objective-Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Key Words: blood pressure Ⅲ endothelial function Ⅲ reactive oxygen species Ⅲ vasodilation Ⅲ NADPH oxidase E ndothelial dysfunction, in particular the impairment of endothelium-dependent vasodilatation, is involved in the pathophysiology of hypertension and atherosclerosis. 1 Increased reactive oxygen species (ROS) production contributes to endothelial dysfunction through the inactivation of endothelium-derived nitric oxide (NO) by superoxide and by ROS-dependent modulation of intracellular signaling pathways.

Intracellular ROS (reactive oxygen species) such as superoxide and H2O2 have been increasingly appreciated to have a role in endothelial pathophysiology. Of the several sources within the vasculature, a family of multi-subunit NADPH oxidases appears to be a predominant contributor of endothelial superoxide. More importantly, this enzyme system is activated by numerous stimuli and is involved in triggering diverse intracellular signalling pathways ('redox-sensitive' signalling pathways) that have a central role in conditions such as endothelial activation and inflammation, cell growth, apoptosis and hypertrophy. Furthermore, NADPH oxidase-derived superoxide contributes to the impairment of endothelium-dependent vasodilatation by inactivating nitric oxide; the resultant endothelial dysfunction is implicated in the pathophysiology of diseases such as atherosclerosis, hypertension, diabetic vasculopathy and heart failure. A detailed understanding of the regulation of NADPH oxidases and their modulation and downstream effects may define novel therapeutic targets for cardiovascular disease prevention and treatment in the clinical setting, in contrast with global antioxidant therapy which has to date been disappointing.