Contribution of Peroxynitrite, a Reactive Nitrogen Species, in the Pathogenesis of Autoimmunity

Peroxynitrite is a member of reactive nitrogen species that also includes nitric oxide (·NO) and nitrogen dioxide radical (NO2). Peroxynitrite is a reactive nitrogen species and an anion with the formula (ONOO−). It is an unstable ‘valence isomer’ of nitrate (NO3−), making it an oxidant and nitrating agent. Because of its oxidizing properties, peroxynitrite can damage a wide range of molecules in cells, including DNA and proteins (1). It is produced by the body in response to a variety of environmental toxins, stress, ultraviolet light and many other stimuli. It is also produced in the body due to ischemia/ reperfusion injury and inflammation (2, 3). In vivo, peroxynitrite is formed in the macrophages, endothelial cells, platelets, leukocytes, neurons, etc by the reaction between O2 – and ·NO (4, 5). Tissue inflammation and chronic infection lead to the overproduction of ·NO and O2·–, which rapidly combine to yield peroxynitrite: O2 – + ·NO → ONO2−. Endothelial ·NO synthase (eNOS) is responsible for most of the vascular ·NO produced. The eNOS oxidizes its substrate L-arginine to L-citrulline and ·NO. A functional eNOS requires dimerization of the enzyme, the substrate L-arginine, and an essential cofactor, BH4 (5,6,7,8-tetrahydro-Lbiopterin). The O2 – produced can react with vascular ·NO to form peroxynitrite. Diminished levels of BH4 promote O2 – production by eNOS. The transformation of eNOS from a vasoprotective enzyme to a contributor to oxidative stress has been observed in several in vitro systems, animal models of cardiovascular diseases and in patients with cardiovascular risk factors (6). In inflammation or septic shock, ·NO is also synthesized by the inducible ·NO synthase (iNOS), an isoform that is expressed in many cell types including vascular endothelial cells, vascular smooth muscle and inflammatory cells in response to pro-inflammatory cytokines. Peroxynitrite, can be formed intravascularly in various disease conditions when there is overproduction of either ·NO or O2 – (7). The intravascular formation of peroxynitrite can result in oxidative modifications of plasma and vessel wall proteins including the formation of protein-3-nitrotyrosine. Protein tyrosine nitration in plasma or vessel wall proteins may be indicative of peroxynitrite formation, and constitutes a good biomarker of ·NO-derived oxidant production in the vascular space. Detection of 3-nitrotyrosine in vivo has attracted considerable interest not only as a biomarker of peroxynitrite formation but also as a predictor of vascular risk (8).