Oxidant-induced signaling: Effects of peroxynitrite and singlet oxygen

Following the requirement for cells to cope with oxidative stress, there are cellular adaptation mechanisms at the level of gene expression. Much of what is known about oxidant-induced signaling in mammalian cells was found in experiments using hydrogen peroxide as an oxidant. However, since the biochemical reactivities of various oxidants significantly differ, 'oxidative stress' is not necessarily identical independent of the oxidant employed to bring it about. Here, the biological actions of peroxynitrite and singlet oxygen are presented, focusing on signaling effects. Peroxynitrite is generated in biological systems in the diffusion-controlled reaction of superoxide with nitrogen monoxide and is thus likely to be produced in the vicinity of activated macrophages. Singlet oxygen is generated by stimulated neutrophils in vivo and may further be generated photochemically, e.g. upon exposure of cells to ultraviolet A radiation. Exposure of cells to either of these oxidants elicits a cellular stress response, entailing the activation of signaling cascades that regulate proliferative and apoptotic responses, such as mitogen-activated protein kinase cascades or the phosphoinositide 3-kinase/Akt cascade. Two mechanisms for the oxidant-induced activation of a signaling cascade may be envisaged: (i) the indirect targeting of the cascade by interrupting negative regulation, and (ii) an activating oxidation of one of the constituting components of the cascade. Examples for both mechanisms in relation to peroxynitrite and singlet oxygen are discussed.