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.

Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses, but the role of different ROS sources remains unclear. Here we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level, which increases in cardiomyocytes under stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models, but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte hypoxia inducible factor 1 and the release of vascular endothelial growth factor, resulting in increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of nonspecific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings.cardiac remodeling | hypoxia inducible factor | reactive oxygen species

Abstract-Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O 2 Ϫ production in LV homogenates, measured by lucigenin (5 mol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by Ϸ40% at the stage of LV decompensation; PϽ0.05). O 2 Ϫ production was fully inhibited by diphenyleneiodonium (100 mol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22 phox , gp91 phox , p67 phox , and p47 phox in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O 2 Ϫ production, there was a significant increase in activation of extracellular signal-regulated kinase 1/2, extracellular signal-regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure. Key Words: hypertrophy Ⅲ free radicals Ⅲ heart failure Ⅲ myocardium Ⅲ reactive oxygen species A n increase in oxidative stress resulting from increased cardiac generation of reactive oxygen species (ROS) is implicated in the pathophysiology of pressure-overload left ventricular hypertrophy (LVH) and congestive heart failure, both experimentally and in clinical studies. 1-3 Increased ROS production is implicated in the development of cellular hypertrophy and remodeling, at least in part through activation of redox-sensitive protein kinases such as the mitogenactivated protein kinase (MAPK) superfamily. The transition from compensated pressure-overload LVH to heart failure is associated with increased oxidative stress, which may promote myocyte apoptosis and necrosis. Several key proteins involved in excitation-contraction coupling, such as sarcolemmal ion channels and exchangers and sarcoplasmic reticulum calcium release channels, can undergo redoxsensitive alterations in activity, which contributes to myocardial contractile dysfunction. ROS also has indirect effects resulting from increased inactivation of NO and consequent generation of peroxynitrite, eg, coronary vascular endothelial dysfunction and peroxynitrite-induced inhibition of myocardial respiration. 4 The sources of ROS generation that contribute to these effects in pressure-overload LVH and heart failure remain poorly defined. Potential sources include the mitochondrial electron transport chain, xanthine oxida...