Endosomal ClC-3 and Nox1

Despite tremendous advances in our knowledge of the role of oxidative species in vascular disease, much debate remains regarding the mechanism by which NADPH oxidases (Nox) impart specific effects in cells. Over the past 2 decades, the term oxidative stress has often been used to describe the effects of Nox-derived reactive oxygen species (ROS). Much credence was initially given to relatively large quantities of ROS as mediators of myriad and varied cellular responses, ranging from connective tissue expression to differentiation, hypertrophy, proliferation, and apoptosis.1 With the discovery of multiple Nox isoforms and emergence of loss-of-function and gain-of-function technologies manipulating the levels of individual isoforms, a large body of literature emerged suggesting that small, localized ROS derived from individual Nox proteins can impart unique cellular responses. The lack of sophisticated detection methods for localizing perhaps subtle changes in ROS continues to stymie our understanding of how one Nox may confer activation of a specific signaling cascade and render distinct cell changes. The conundrum of why similar whole cell or tissue increases or decreases in ROS confer disparate phenotypes continues to confound leaders in the field.See accompanying article on page 345One such phenotypic change with broad implication for human disease is vascular smooth muscle cell (SMC) hyperplasia and neointimal growth. Central to neointimal formation is the proliferation and migration of SMCs, processes in which ROS and matrix metalloproteinase activation are established factors.2–5 It is now broadly accepted that (1) inflammation plays an important role in atherosclerosis and SMC activation, which leads to neointimal formation,2 and (2) cytokines, such as tumor necrosis factor-α (TNF-α), are important mediators in this response6,7. Indeed, inflammatory …