Nitric oxide and its role in apoptosis.

Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of diverse (patho)physiological processes. It is appreciated that the production of NO. from L-arginine is important for nonspecific host defense, helping to kill tumors and intracellular pathogens. Cytotoxicity as a result of a massive NO.-formation is now established to initiate apoptosis. Apoptotic cell death in RAW 264.7 macrophages and several other systems as a result of inducible NO-synthase activation comprises upregulation of the tumor suppressor p53, activation of caspases, chromatin condensation, and DNA fragmentation. The involvement of NO was established by blocking adverse effects by NO-synthase inhibition. Overexpression of the antiapoptotic protein Bcl-2 rescued cells from apoptosis by blocking signal propagation downstream of p53 and upstream of caspase activation. As the wide variety of NO.-effects is achieved through its interactions with targets via redox and additive chemistry, the biological milieu, as a result of internal and external stimuli, may modulate toxicity. Therefore, transducing pathways of NO. are not only adopted to cytotoxicity but also refer to cell protection. NO.-signaling during protection from apoptosis is in part understood by the requirement of gene transcription and protein synthesis. NO.-formation causes upregulation of protective proteins such as heat shock proteins, cyclooxygenase-2, or heme oxygenase-1 which in a cell specific way may attenuate apoptotic cell death. Alternatively, protection may result as a consequence of a diffusion controlled NO./O2- (superoxide) interaction. The NO./O2--interaction redirects the apoptotic initiating activity of either NO. or O2- towards protection as long as reduced glutathione compensates the resultant oxidative stress. Protective principles may further arise from cyclic GMP formation or thiol modification. NO shares with other toxic molecules such as tumor necrosis factor-alpha the unique ability to initiate and to block apoptosis, depending on multiple variables that are being elucidated. The crosstalk between cell destructive and protective signaling pathways, their activation or inhibition under the modulatory influence of NO. will determine the role of NO in apoptotic cell death.