H 2 O 2 -induced O⨪ 2 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 O⨪ 2, which is subsequently converted to H 2 O 2 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 H 2 O 2 activates these cell types to produce O⨪ 2 via an NAD(P)H oxidase. The ensuing endogenous production of O⨪ 2 contributes significantly to vascular cell injury following exposure to H 2 O 2. These results suggest the existence of a feed-forward mechanism, whereby reactive oxygen species such as H 2 O 2 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.