Increased Circulating Levels of 3-Nitrotyrosine Autoantibodies

3-nitrotyrosine formation is an oxidative protein modification that was first discovered in vivo in the early 1990s by Beckman and colleagues.1,2 The biological relevance of this process was extensively investigated in the subsequent years and further facilitated by the development of 3-nitrotyrosine–specific antibodies.3 Protein tyrosine nitration is mainly mediated by 3 biochemical processes (Figure): (1) by peroxynitrite (ONOO−) formation,4–6 the reaction product of nitric oxide (•NO) and superoxide (•O2−); (2) by a (myelo)peroxidase-catalyzed nitrogen dioxide radical (•NO2) formation from hydrogen peroxide and nitrite;7,8 and (3) by a nonspecific formation of the nitrogen dioxide radical from nitric oxide in oxygenated buffers (reflecting rather artificial ex vivo conditions).Figure. Scheme illustrating antibody (IgG) formation against 3-nitrotyrosine-positive proteins and their involvement in the initiation and propagation of coronary artery disease (CAD). Under physiological conditions, the vascular integrity is mainly guaranteed by nitric oxide (•NO) and prostacyclin (PGI2), causing vasodilation, antiaggregation, anti-inflammation, and intact endothelial barrier function. In the presence of cardiovascular risk factors such as hypertension, chronic smoking, hypercholesterolemia, and diabetes mellitus, there is increased formation of superoxide (•O2−) or increased myeloperoxidase (MPO) activity, with the consequence that •NO is consumed to form peroxynitrite (ONOO−) or nitrogen dioxide radical (•NO2). Peroxynitrite or nitrogen dioxide radical in turn cause tyrosine nitration of prostacyclin synthase (PGIS), with the consequence of reduced prostacyclin formation (PGI2) but also enhanced formation of the vasoconstrictor …