H2O2-induced O-2(radical anion) 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 re active oxygen species in blood vessels. These oxidases can be activated by cytokines, thereby generating O-2(radical anion), which is subsequently con verted to H2O2 and other oxidant species. The oxidants, in turn, act as imp ortant second messengers in cell signaling cascades. We hypothesized that r eactive 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 o f non-phagocytic cell types of vascular origin (smooth muscle cells and fib roblasts) to H2O2 activates these cell types to produce O-2* via an NAD(P)H oxidase. The ensuing endogenous production of O-2* contributes significant ly to vascular cell injury following exposure to H2O2. These results sugges t the existence of a feed-forward mechanism, whereby reactive oxygen specie s such as H2O2 can activate NAD(P)H oxidases in non-phagocytic cells to pro duce additional oxidant species, thereby amplifying the vascular injury pro cess. Moreover, these findings implicate the non-phagocytic NAD(P)H oxidase as a novel therapeutic target for the amelioration of the biological effec ts of chronic oxidant stress.