XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Nitric oxide conveys crucial signals that result in a wide spectrum of effects such as vasodilatation, modulation of neurotransmission, host defense in the immune response, gene expression and mitochondrial function.

Stockholm, Sweden -- Dr S. Moncada (Strategic Medical Research, London, UK) summarized the status of nitric oxide (NO), a molecule that a little over a decade after its discovery has proven its significant biological importance. Not only does it convey crucial signals that result in a wide spectrum of effects such as vasodilatation, modulation of neurotransmission and host defense in the immune response, but also it acts as an important regulator of general cellular processes such as gene expression and mitochondrial function.

NO and mitochondrial function
One of the ways in which NO could evolve from a physiological mediator to a pathological player might be through its actions on mitochondrial function. Physiological concentrations of NO inhibit cytochrome c oxidase (complex IV) in a reversible manner, in competition with oxygen. This could represent a physiological strategy to reduce O₂ consumption without affecting ATP production. However, long-term exposure to NO can irreversibly inhibit mitochondrial complex I. Whether the action of NO on complex I is due to NO itself or to some related species is not yet clear. The mitochondria are a source of superoxide anion (O^2-) which can rapidly react with NO to form peroxynitrite (ONOOO-). Referring to a paper by Belén Beltrán (British J Pharmacol 2000, 129:953), Dr Moncada suggested that the persistent impairment of complex I by S-nitrosylation might represent a turning point in the cell that leads to a pathophysiological inhibition of complex I. Indeed inhibition of complex I has toxic effects and leads to the triggering of an apoptotic program.

NO and atherogenesis
Immunohistochemical studies demonstrate the expression of inducible nitric oxide synthase (NOS II) in human and experimental atherosclerosis. NOS II was found in macrophage-derived foam cells in fatty streaks of the human aorta. NO may exert antiatherogenic properties through inhibition of oxidative process, monocyte recruitment, and proliferation of T cells and smooth muscle cells. High doses of NO, however, might be atherogenic via stimulation of apoptosis and matrix breakdown, and by the formation of the cytotoxic peroxynitrite. This strong oxidant, which is formed when NO reacts with superoxide anion, might initiate peroxidation of polyunsaturated fatty acids, as indicated by the formation of F2 isoprostanes when plasma or human low-density lipoproteins are exposed to peroxynitrite. The study by Cromheeke (Cardiovasc Res 1999, 43:744) shows that NOS II is present in the advanced plaques in macrophages that also contain nitrated proteins. Nitrotyrosine and nitrated proteins are considered signs of the formation and activity of the NO-derived oxidant peroxynitrite. Colocalization of NOS II and nitrotyrosine indicates that NOS is enzymatically active and that the produced NO reacts with superoxide O^2- to form peroxynitrite (OONO^-) which then nitrates tyrosine residues of proteins. NO or peroxynitrite might lead to plaque destabilization by the induction of cell death and matrix breakdown.