Mechanosensitive Regulation of Cortactin by p47 phox

Abstract

p47phox is 1 of the 5 subunits that makes up the multisubunit complex of the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2), a major source of cellular reactive oxygen species (ROS).1 The prototype Nox2 comprises 2 transmembrane subunits (gp91phox [Nox2] and p22phox) and 3 cytosolic subunits (p47phox, p67phox, and p40phox).2,3 Nox2 is characteristically found in phagocytic cells, where it has a critical antimicrobial function through the production of superoxide anion.2 Nox2, as well as the other Nox homologues, including Nox1, Nox4, and Nox5, is expressed in many cell types, including those of the cardiovascular system.3 Although the function of phagocytic Nox2 is clearly defined, the exact pathophysiological significance of cardiovascular Nox2 is still unclear. Article, see p 1542 p47phox is a major regulator of Nox2.1 In the resting state, it localizes in the cytoplasm where its activity is inhibited through an autoinhibitory phosphorylation. However, on cell stimulation, p47phox interacts with cytosolic subunits p67phox and p40phox and the complex translocates to the cell membrane to assemble the active oxidase, which generates superoxide anion.2 This process is triggered by phosphorylation of p47phox, which is the key for activation of Nox and consequent ROS production. Upregulation of Nox and associated increased ROS generation (oxidative stress) have been implicated in many cardiovascular pathologies, processes that are p47phox dependent because deletion of this subunit reduces oxidative stress and ameliorates pathological cardiac and vascular inflammation and remodeling.4–7 On the basis of this paradigm, in this issue of Circulation Research , Patel et al8 questioned the putative protective effect of p47phox deletion/downregulation in a mouse model of transverse aortic constriction–induced pressure overload and heart failure. Intriguingly and …