Protection from the Dark Side of NO: Signaling and Cellular Defenses Against Nitric Oxide Toxicity

Although it is employed in biological systems for intercellular signaling or inflammatory responses, nitric oxide is not readily contained by cell membranes and so might damage surrounding non-target cells. We have studied the genetic and biochemical basis of cellular resistance to the toxicity of NO. Inducible resistance mechanisms activate defense pathways that diminish lethal damage, prevent apoptosis, and may employ increased repair systems. A key inducible component of the cell response to NO toxicity is the enzyme heme oxygenase-1 (HO1). The activity of HO1 is necessary for the basic resistance of mammalian cells to NO-mediated cytotoxicity. However, the critical HO1-dependent reaction(s) responsible for NO resistance have not yet been identified. The induction of HO1 in response to NO depends on limited transcriptional activation and, in some cell types, on dramatic NO-induced stabilization of the HO1 mRNA. In human fibroblasts, this stabilization increases directly with the degree of NO exposure. Novel regulatory pathways appear to underlie the pathways of inducible NO resistance and NO-mediated mRNA stability.