H₂O₂-induced O₂^.- Production by a Non-phagocytic NAD(P)H Oxidase Causes Oxidant Injury

Non-phagocytic NAD(P)H oxidases have been implicated as major sources of reactive oxygen species in blood vessels. These oxidases can be activated by cytokines, thereby generating O₂^.-, which is subsequently converted to H₂O₂ and other oxidant species. The oxidants, in turn, act as important second messengers in cell signaling cascades. We hypothesized that reactive oxygen species, themselves, can activate the non-phagocytic NAD(P)H oxidases in vascular cells to induce oxidant production and, consequently, cellular injury. The current report demonstrates that exogenous exposure of non-phagocytic cell types of vascular origin (smooth muscle cells and fibroblasts) to H₂O₂ activates these cell types to produce O₂^.- via an NAD(P)H oxidase. The ensuing endogenous production of O₂^.- contributes significantly to vascular cell injury following exposure to H₂O ₂. These results suggest the existence of a feed-for. ward mechanism, whereby reactive oxygen species such as H₂O₂ can activate NAD(P)H oxidases in non-phagocytic cells to produce additional oxidant species, thereby amplifying the vascular injury process. Moreover, these findings implicate the non-phagocytic NAD(P)H oxidase as a novel therapeutic target for the amelioration of the biological effects of chronic oxidant stress.