Knock, knock: who's there?: Nox1

It has become apparent that major sources of reactive oxygen species (ROS) in mammalian cells are the NADPH oxidases. These multimeric enzymes are composed of membrane-bound catalytic subunits, or Nox enzymes, and a small docking subunit called p22phox. Depending on the Nox isoform, cytosolic regulatory subunits also play a role in their activation. There are 7 Nox isoforms. The first identified was Nox2, also called gp91 phox , which is present in phagocytic cells and is responsible for the oxidative burst. Unlike Nox2, the other Nox enzymes exhibit sustained production of ROS at somewhat lower levels. Their modes of activation differ, as do their cellular distributions. Nox1 through Nox4 are expressed in vascular cells in rodents. Nox5 has been identified in atherosclerotic lesions of humans but is not expressed in rodents. Stimulation of cells with angiotensin II, cytokines, catecholamines, high glucose, or mechanical stretch promotes NADPH oxidase activation, in large part as a result of recruitment of cytosolic subunits to the membrane subunit, leading to the formation of the functional enzyme complex that can transfer electrons to molecular oxygen and the formation of superoxide (O2·−).1 O2·−serves as a progenitor for other ROS, including hydrogen peroxide, peroxynitrite, and hypochlorous acid. Enhanced activity of the NADPH oxidases and increased expression of its subunits occur in many pathological conditions, including hypertension, diabetes mellitus, atherosclerosis, cardiac hypertrophy, and heart failure. Studies of genetically altered mice have shown that the deletion of various NADPH oxidase subunits protects against these diseases and their overexpression promotes pathology.2−4 Article see p 1888 A consequence of excessive ROS formation is loss of endothelial nitric oxide (NO), which can occur by rapid radical-radical reactions with O2·− and other radicals or as a result of dysfunction of the endothelial NO synthase. …