Associate editor: A. ChristopoulosNADPH oxidases in the vasculature: Molecular features, roles in disease and pharmacological inhibition
Section snippets
Introduction: reactive oxygen species: roles in physiology and pathophysiology
Life as an aerobic organism is a double-edged sword. On the one hand, oxygen is an abundant source of readily available and transferable energy that supports the complex array of biochemical reactions required for even the most basic of cellular functions. On the other hand, oxygen is an oxidising agent that could potentially damage the cellular infrastructure (e.g. nucleotides, proteins, lipids and carbohydrates) required for these very same processes. In actuality, ground state molecular
NADPH oxidases are major sources of reactive oxygen species in blood vessels
Within mammalian cells, several enzyme systems are capable of transferring electrons to molecular oxygen to produce superoxide, including NADH dehydrogenase and ubiquinone–cytochrome bc1 of the mitochondrial electron transport chain (Boveris and Cadenas, 1975, Turrens, 2003, Orrenius et al., 2007), nitric oxide synthases (NOS) (Vasquez-Vivar et al., 1998, Vasquez-Vivar and Kalyanaraman, 2000, Alp and Channon, 2004), cyclooxygenases (Simmons et al., 2004), lipoxygenases (Wittwer & Hersberger,
Molecular description of vascular NADPH oxidases
The purpose of the present discussion is not to provide an exhaustive review of the molecular biology and biochemistry of the various NADPH oxidase family members. Indeed this has been achieved recently in several excellent reviews (Vignais, 2002, Groemping and Rittinger, 2005, Sumimoto et al., 2005). Rather, here we aim to highlight some of the key molecular sites involved in activation of the NADPH oxidases, especially those, which are unique to specific isoforms, and may therefore be
Cellular and subcellular localisation of NADPH oxidase isoforms in the vascular wall
ROS have been implicated in numerous processes associated with atherogenesis including endothelial dysfunction, activation of inflammatory signalling pathways, upregulation of adhesion molecules, proliferation of vascular smooth muscle cells and oxidation of lipoproteins. Hence, identification of the cellular and enzymatic source(s) of ROS that contribute to each of these processes is essential for the development of effective therapies to reduce vascular oxidative stress and its many sequelae.
NADPH oxidases: causes and not just symptoms of vascular disease
The previous discussion, based largely on in vitro observations, suggest that Nox4-oxidases and constitutively active isoforms of Nox2-oxidases are important sources of intracellular ROS in the cells of the vascular wall under basal conditions. By contrast, in pathophysiological settings, inducible isoforms of Nox1- (in VSMCs) and Nox2- (in endothelial cells, fibroblasts and invading phagocytes) oxidases are upregulated. Importantly, these observations are generally supported in vivo. Hence, in
Inhibitors of NADPH oxidase and their limitations
The recent emergence of evidence implicating Nox enzymes in oxidative stress-related disorders of the cardiovascular system highlights the substantial clinical potential of Nox inhibitors. However, clearly much remains to be learned about the function and tissue distribution of these enzymes, and the stimuli which activate them. Furthermore, given that Nox enzymes have different subcellular locations and are likely to influence the redox milieu of cells, it is critical that Nox inhibitors do
Pleiotropic actions of three commonly employed cardiovascular drug classes
A number of clinically important drugs used for the treatment of hypertension, hypercholesterolaemia and coronary artery disease such as the statins, AT1 receptor antagonists and the ACE inhibitors have been shown to decrease NADPH oxidase-derived superoxide and ROS production, and thus are likely to mediate some of their beneficial actions via these mechanisms. The purpose of this section is not to provide an exhaustive review of these classes of drugs but to highlight briefly how these
Perspectives
From the previous discussion of the various currently available inhibitors, it is apparent that none of these compounds show any specificity towards a particular isoform of NADPH oxidase (Table 1). Nevertheless, these compounds are valuable for assessing the roles of these enzyme systems in in vitro and in vivo assays. For example, we suggest that if the intention of a study was to inhibit superoxide/ROS production generated by all NADPH oxidases within a particular in vitro system (i.e. cell
Concluding remarks
NADPH oxidases are ubiquitously expressed across many phyla and species and subserve a range of crucial redox-sensitive physiological and biological functions through the generation of ROS. The processes that lead to NADPH oxidase activation are complex and finely regulated; however, dysregulation of its expression and activation coupled with unregulated or inefficient ROS removal often leads to oxidative stress and an altered cellular phenotype, contributing to development of major
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