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 appre ciated that the production of NO. from L-arginine is important for non specific host defense, helping to kill tumors and intracellular pathog ens. Cytotoxicity as a result of a massive NO.-formation is now establ ished to initiate apoptosis. Apoptotic cell death in RAW 264.7 macroph ages and several other systems as a result of inducible NO-synthase ac tivation comprises upregulation of the tumor suppressor p53, activatio n of caspases, chromatin condensation, and DNA fragmentation. The invo lvement of NO. was established by blocking adverse effects by NO-synth ase inhibition. Overexpression of the antiapoptotic protein Bcl-2 resc ued cells from apoptosis by blocking signal propagation downstream of p53 and upstream of caspase activation. As the wide variety of NO.-eff ects is achieved through its interactions with targets via redox and a dditive chemistry, the biological milieu, as a result of internal and external stimuli, may modulate toxicity. Therefore, transducing pathwa ys 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 synthe sis. 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, p rotection may result as a consequence of a diffusion controlled NO./O- 2(-) (superoxide) interaction. The NO./O-2(-)-interaction redirects th e apoptotic initiating activity of either NO. or O-2(-) towards protec tion as long as reduced glutathione compensates the resultant oxidativ e stress. Protective principles may further arise from cyclic GMP form ation or thiol modification. NO. shares with other toxic molecules suc h as tumor necrosis factor-alpha the unique ability to initiate and to block apoptosis, depending on multiple variables that are being eluci dated. The crosstalk between cell destructive and protective signaling pathways, their activation or inhibition under the modulatory influen ce of NO. will determine the role of NO. in apoptotic cell death. (C) 1998 Elsevier Science B.V. All rights reserved.