The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4 and 5), their roles in cardiovascular cell biology, and their contributions to disease development.

Objective-Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models. Methods and Results-Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1 y/Ϫ mice, but there was little difference in Tg SMCnox1 mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1 y/Ϫ VSMCs and increased in Tg SMCnox1 cells. Tg SMCnox1 cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1 y/Ϫ cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1 y/Ϫ cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1 y/Ϫ VSMCs. Conclusions-These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation. (Arterioscler Thromb Vasc Biol. 2009;29:480-487.)Key Words: NADPH oxidase 1 Ⅲ neointima Ⅲ migration Ⅲ vascular smooth muscle Ⅲ reactive oxygen species T he abnormal intimal growth of blood vessels as a "response to injury" is key in the development of vascular occlusive diseases such as in-stent stenosis, intimal proliferation after vein grafts, and atherosclerosis; hence, it is the major limitation for the efficacy of corrective surgery. 1 Vascular smooth muscle cells (VSMCs) are a main constituent of the neointima in these lesions. After injury, VSMCs migrate to the damaged area, proliferate and elaborate extracellular matrix (ECM), largely in response to platelet-derived growth factor (PDGF) stimulation. 2 The molecular mechanisms underlying these events are poorly understood.Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide mediate signal transduction pathways that contribute to the pathophysiological responses of VSMCs including migration, proliferation, apoptosis, phenotypic modulation, and hypertrophy. 3 Major sources of ROS in VSMCs, especially in pathological conditions, are the NADPH oxidase (Nox) family of enzymes. VSMCs from conduit arteries express Nox1 and Nox4, 4 whereas those from resistance arteries express Nox2 and Nox4. 5 These oxidases serve different functions within the cells, 6 presumably owing to their distinct intracellular compartmentalization and different mechanism of regulation and activation. 7 Of interest, studies have linked Nox1 to VSMC phenotypic changes including angiotensin II-...

Endothelial dysfunction is associated with atherogenesis and oxidative stress in humans. In rat and rabbit blood vessels, wine polyphenol antioxidants induce vascular relaxation in vitro through the NO-cGMP pathway. To assess the effect of a regular high-fat diet (HFD) and moderate red wine consumption on endothelial function (EF), a study was performed in healthy male volunteers. EF was measured as flow-mediated dilatation of the brachial artery, employing high-resolution ultrasound after an overnight fast. Other clinical and biochemical parameters related to EF were also measured. Six volunteers received a control diet, rich in fruits and vegetables (27% calories as fat) and five volunteers received an HFD (39.5% calories as fat). Measurements were done twice on each volunteer: after a period of 30 d with diet plus 240 mL of red wine/d, and after a period of 30 d with diet, without wine. In the absence of wine, there is a reduction of EF with HFD when compared to the control diet (P = 0.014). This loss of EF is not seen when both diets are supplemented with wine for 30 d (P = 0.001). Plasma levels of n-3 fatty acids (R2 = 0.232, P = 0.023) and lycopene (R2 = 0.223, P = 0.020) show a positive correlation with individual EF measurements, but they do not account for the significant differences observed among dietary groups or after wine supplementation. These results help elucidate the deleterious effect of a high-fat diet and the protective role of wine, n-3 fatty acids and dietary antioxidants in cardiovascular disease.