NADPH Oxidase-2 and Atherothrombosis

Atherothrombosis encompasses a sequence of events whose hallmarks are atherosclerotic plaque formation and the ensuing thrombotic complications at sites of plaque rupture or erosion. Key steps in the atherosclerosis process include accumulation and oxidation of low-density lipoproteins (LDLs) by reactive oxygen species (ROS) within the artery wall and perpetuation of the inflammatory process via infiltration of monocyte–macrophages, which become foam cells on uptake of oxidized LDL. The atherosclerosis process eventually can result in rupture or erosion of the arterial wall with subsequent platelet aggregation locally and thrombus formation, known as atherothrombosis, resulting in occlusion of blood flow and downstream cellular damage. ROS are implicated in the process of atherothrombosis with other mechanisms including arterial dysfunction via NO inactivation or NO synthase inhibition and platelet activation via overexpression of platelet eicosanoids and platelet NO inhibition. Among the enzymatic pathways involved in ROS formation, NADPH oxidase (Nox) is among the most important cellular producers of ROS. The Nox family includes several isoforms including the phagocytic Nox2, which is a key component of the innate immune system because it greatly contributes to bacterial killing. Nox2 is a transmembrane protein whose gp91 and gp22 subunits form a membranebound heterodimeric flavocytochrome b558, which acts as a catalytic core. Nox2 was originally identified in phagocytes, but subsequent studies demonstrated that it is also expressed in endothelial cells, cardiomyocytes, hematopoietic stem cells, and platelets. Activation of Nox2 requires translocation of cytosolic subunits, namely, p47, p67, p40, and Rac1 to the membrane flavocytochrome b558 complex comprising gp91 and p22. Once assembled, Nox2 activation results in electron reduction of oxygen to superoxide anion O .2 ), which rapidly dismutes to hydrogen peroxide and then is converted by neutrophil myeloperoxidase to hypochorous acid (bleach) and then to chlorine. These products are all potent antimicrobial agents. In other cells, ROS exert different activities. For example, O .2 can rapidly react with and inactivate NO thereby impairing its vasodilating property and hydrogen peroxide, reportedly possesses vasodilating and platelet aggregating properties. Patients with the clinical syndrome resulting from loss of function of Nox2, chronic granulomatous disease (CGD), have increased propensity to infection with certain bacteria. CGD is caused by mutations in any of the 4 genes encoding subunits for superoxide anion generation. Approximately 60% CGD patients have hereditary deficiency of the Nox2 subunit glycoprotein gp91 (X-linked CGD), ≈30% have autosomal recessive hereditary deficiency of the Nox2 subunit p47, and most of the remainder of patients have autosomal