Nitric oxide as a bioregulator of apoptosis

Nitric oxide (NO), synthesized from L-arginine by NO synthases, is a small, diffusible, highly reactive molecule with dichotomous regulatory roles und er physiological and pathological conditions. NO can promote apoptosis (pro apoptosis) in some cells, whereas it inhibits apoptosis (antiapoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as iron, thiols, protein s, and reactive oxygen species. Long-lasting production of NO acts as a pro apoptotic modulator by activating caspase family proteases through the rele ase of mitochondrial cytochrome c into the cytosol, upregulation of p53 exp ression, activation of JNK/SAPK, and altering the expression of apoptosis-a ssociated proteins including Bcl-2 family proteins. However, low or physiol ogical concentrations of NO prevent cells from apoptosis induced by trophic factor withdrawal, Fas, TNF alpha, and lipopolysaccharide. The antiapoptot ic mechanism can be understood via expression of protective genes such as h eat shock proteins, Bcl-2 as well as direct inhibition of the apoptotic cas pase family proteases by S-nitrosylation of the cysteine thiol. Our current understanding of the mechanisms by which NO exerts both pro-and antiapopto tic actions is discussed in this review article. (C) 2001 Academic Press.