Nitric Oxide and Apoptosis

Low doses of NO inhibited apoptosis in human B lymphocytes (Mannick et al. 1994, Genaro et al. 1995). In contrast, NO functions as an apoptotic inducer for macrophages, hepatocytes, neurones and ghal cells. The proapoptotic activity of NO is mediated via the release of mitochondrial cytochrome c into the cytosol, the sequential loss of mitochondrial membrane potential, and the activation of members of the caspase family of proteases (Ue-HARA et al. 1999, Brookes et al. 2000, Moriya et al. 2000). CiBELLi et al. (2002) analysed the NO- 

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J. Haendeler, A.M. Zeiher, and S. Dimmeler. 1999. Nitric oxide and apoptosis Vitam. Horm. 57 49-77. (PubMed)... 

The lack of zinc can also be a problem in biological systems and is responsible for disease states. For example, nitric oxide-dependent apoptosis can be induced in motor neurons by zinc-deficient SOD, and in some cases of amyotrophic lateral sclerosis, zinc-deficient SOD may participate in this type of oxidative mechanism involving nitric oxide.969 One form of hereditary human hair loss or alopecia was mapped to a specific gene and a mutation found in affected individuals. The gene encodes a single zinc finger transcription factor protein with restricted expression in the brain and skin.970 Zinc has been implicated in Alzheimer s via beta amyloid formation, and a role has been attributed for the cerebral zinc metabolism in the neuropathogenesis of Alzheimer s disease.971... 

In conclusion, it should be stressed that the competition between pro- and antiapoptotic effects of nitric oxide must probably depends on its relevant levels [137] the low physiological levels of NO principally suppress the apoptotic pathway by several mechanisms, whereas the higher rates of NO production may overcome cellar protective mechanisms and stimulate apoptosis. Furthermore, the simultaneous formation of nitric oxide and superoxide increases the possibility of apoptosis activation due to the formation of peroxynitrite. 

Messmer, U.K. and Brune, B., Nitric oxide-induced apoptosis p53-depedent and p53-inde-pendent signalling pathways, Biochem. J., 319, 299, 1995. 

Nitric oxide-induced apoptosis in human leukemic lines requires mitochondrial hpid degradation and cytochrome c release. Blood 93 2342-2352. 

Nitric-oxide-induced apoptosis in human leukemic lines requires mitochondrial Upid degradation and cytochrome c lelease. Blood, 93 2342-2352 Wendel, A., 1981, Glutathione peroxidase. Methods Enzymol. 77 325-333... 

Albina, J.E., Cui, S., Mateo, R.B., and Reichner, J.S., 1993, Nitric oxide-mediated apoptosis in murine peritoneal macrophages, JImmunol. 150 5080-5085. 

D. Washo-Stultz, N. Hoglen, H. Bernstein, C. Bernstein and C. M. Payne, Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis relevance to colon carcinogenesis, Nutr. Cancer, 1999, 35(2), 180. 

The origin of this discrepancy is unknown. Cerielo et al. [147] studied the stimulation of apoptosis by acute hyperglycemia in working rat hearts. It was found that high glucose levels raised nitric oxide and superoxide production, which supposedly yielded peroxynitrite the last by itself or through the formation of nitrotyrosine induced apoptosis in rat hearts. 

If the ATP depletion is too great, then apoptosis cannot proceed. Kupffer cell activation involving IFNy (interferon) and TNF-a is part of an inflammatory response in which nitric oxide and various cytokines are produced. 

Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric-oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion. 

PROTECTION BY SELEGILINE AGAINST PEROXYNITRITE- AND NITRIC-OXIDE-INDUCED APOPTOSIS... 

Apoptosis is induced by various intra- and extracellular stimuli, and recently nitric oxide was reported to induce apoptosis in cultured cerebellar granule cells and cultured cortical neurons. The toxicity of nitric oxide is mainly ascribed to peroxynitrite, a reaction product of nitric oxide with superoxide (Figure 13.8). Cells producing an increased amount of SOD (superoxide, superoxide oxidoreductase EC 1.15.1.1) are resistant to nitric oxide-mediated apoptosis. In contrast, superoxide levels that have been increased by downregulation of Cu,Zn-SOD lead to apoptotic cell death in PC 12 cells, which required the reaction with nitric oxide to generate peroxynitrite. Peroxynitrite itself was found to induce apoptosis in PC12 cells and in cultured cortical neurons. 

VEGF promotes endothelial cell growth and stimulates endothelial cell production of factors such as nitric oxide and prostacycline. VEGF is a chemotactic factor and increases vascular permeability, causing edema. VEGF inhibits apoptosis by the upregulation of apoptosis inhibitors. All of these properties, which are illustrated in Figure I, are mediated by nitric oxide-dependent pathways. 

Pollman, M. J., Yamada, T., Horiuchi, M., et al. 1996. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. Circ Res 79 748-756. 

Other possible mechanisms contributing to AT2-mediated apoptosis include the initiation of a pathway involving both nitric oxide and p53 (Bonnet et al. 2001) and another pathway requiring p38 MAP kinase (Miura and Karnik 2000). There is also evidence that AT2 activation is coupled to the dephosphorylation of STAT (Steckelings et al. 2005). Recently, Miura and coworkers (Miura and Karnik 2000 Miura et al. 2005) reported that the AT2 receptor is capable of inducing apoptosis in R3T3 cells without the need of a ligand. 

Boyd CS, Cadenas E (2002) Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis. Biol Chem 383 411-423... 

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