3-nitrotyrosine and Disease

Protein and lipid nitration represent novel footprints of oxidative and nitrative stress processes. In this review, we first discuss the mechanisms of formation of protein 3-nitrotyrosine and nitrated fatty acids as well as their key biological and signaling actions. Elevation of protein 3-nitrotyrosine levels is associated to tissue injury, and some specific nitrated proteins play a causative role in disease progression; on the other hand, the substantiation on the role of tyrosine nitration on redox signaling is rather scarce. Herein, we also provide evidence to support that the nitration of lipids (i.e. to nitrofatty acids) results in the formation of novel endogenous modulators of redox processes, partially counteracting pro-inflammatory effects of oxidant exposure.

Topics: Animals; Disease; Humans; Lipid Metabolism; Oxidation-Reduction; Proteins; Signal Transduction; Tyrosine

The nitration of free tyrosine or protein tyrosine residues generates 3-nitrotyrosine the detection of which has been utilised as a footprint for the in vivo formation of peroxynitrite and other reactive nitrogen species. The detection of 3-nitrotyrosine by analytical and immunological techniques has established that tyrosine nitration occurs under physiological conditions and levels increase in most disease states. This review provides an updated, comprehensive and detailed summary of the tissue, cellular and specific protein localisation of 3-nitrotyrosine and its quantification. The potential consequences of nitration to protein function and the pathogenesis of disease are also examined together with the possible effects of protein nitration on signal transduction pathways and on the metabolism of proteins.

Topics: Animals; Disease; Humans; Nitrates; Proteins; Signal Transduction; Tyrosine

Although different theories have been proposed to explain the aging process, it is generally agreed that there is a correlation between aging and the accumulation of oxidatively damaged proteins, lipids, and nucleic acids. Oxidatively modified proteins have been shown to increase as a function of age. Studies reveal an age-related increase in the level of protein carbonyl content, oxidized methionine, protein hydrophobicity, and cross-linked and glycated proteins as well as the accumulation of less active enzymes that are more susceptible to heat inactivation and proteolytic degredation. Factors that decelerate protein oxidation also increase the life span of animals and vice versa. Furthermore, a number of age-related diseases have been shown to be associated with elevated levels of oxidatively modified proteins. The chemistry of reactive oxygen species-mediated protein modification will be discussed. The accumulation of oxidatively modified proteins may reflect deficiencies in one or more parameters of a complex function that maintains a delicate balance between the presence of a multiplicity of prooxidants, antioxidants, and repair, replacement, or elimination of biologically damaged proteins.

Topics: Aging; Amino Acids; Animals; Antioxidants; Apoptosis; Cross-Linking Reagents; Cysteine; Disease; Humans; Longevity; Methionine; Models, Biological; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Peptides; Peroxynitrous Acid; Protein Denaturation; Proteins; Rats; Reactive Oxygen Species; Tyrosine

The formation of peroxynitrite and nitrotyrosine was examined in a variety of in vitro and in vivo animal models and its relation to cell or tissue damage was examined. polymorphonuclear leukocyte (PMN)-induced injury to cardiac myocytes endothelial cells, activated PMN produced peroxynitrite. Peroxynitrite appears to be responsible for the injury but it was not a major mediator of endothelial cell injury. In the experiment of ischemia-reperfusion injury of the rat brain nitrotyrosine was formed in the peri-infarct and core-of infarct regions. The degradation curve of nitrotyrosine revealed that its t(1/2) was about 2.2 hours. In the radiation-induced lung injury of rats, nitrotyrosine was also formed but it was not the sole mechanism for the injury. Levels of nitrotyrosine correlated with the severity of myocardial dysfunction in the canine model of cytokine-induced cardiac injury. Inhibition of NO generation abolished the formation of peroxynitrite and nitrotyrosine in all experiments. In conclusion; although nitrotyrosine is formed in a variety of pathological conditions where the generation of NO is increased, its presence does not always correlate with the severity of injury.

Topics: Animals; Brain Ischemia; Cell Survival; Cells, Cultured; Coculture Techniques; Disease; Dogs; Endothelium, Vascular; Lung Diseases; Male; Myocardium; Neutrophils; Radiation Injuries; Rats; Reperfusion Injury; Tyrosine

Nitric oxide, a gaseous free radical, is poorly reactive with most biomolecules but highly reactive with other free radicals. Its ability to scavenge peroxyl and other damaging radicals may make it an important antioxidant in vivo, particularly in the cardiovascular system, although this ability has been somewhat eclipsed in the literature by a focus on the toxicity of peroxynitrite, generated by reaction of O2*- with NO* (or of NO- with O2). On balance, experimental and theoretical data support the view that ONOO- can lead to hydroxyl radical (OH*) generation at pH 7.4, but it seems unlikely that OH* contributes much to the cytotoxicity of ONOO-. The cytotoxicity of ONOO- may have been over-emphasized: its formation and rapid reaction with antioxidants may provide a mechanism of using NO* to dispose of excess O2*-, or even of using O2*- to dispose of excess NO*, in order to maintain the correct balance between these radicals in vivo. Injection or instillation of "bolus" ONOO- into animals has produced tissue injury, however, although more experiments generating ONOO- at steady rates in vivo are required. The presence of 3-nitrotyrosine in tissues is still frequently taken as evidence of ONOO- generation in vivo, but abundant evidence now exists to support the view that it is a biomarker of several "reactive nitrogen species". Another under-addressed problem is the reliability of assays used to detect and measure 3-nitrotyrosine in tissues and body fluids: immunostaining results vary between laboratories and simple HPLC methods are susceptible to artefacts. Exposure of biological material to low pH (e.g. during acidic hydrolysis to liberate nitrotyrosine from proteins) or to H2O2 might cause artefactual generation of nitrotyrosine from NO2- in the samples. This may be the origin of some of the very large values for tissue nitrotyrosine levels quoted in the literature. Nitrous acid causes not only tyrosine nitration but also DNA base deamination at low pH: these events are relevant to the human stomach since saliva and many foods are rich in nitrite. Several plant phenolics inhibit nitration and deamination in vitro, an effect that could conceivably contribute to their protective effects against gastric cancer development.

Topics: Animals; Biomarkers; Disease; Humans; Nitrates; Nitric Oxide; Superoxides; Tyrosine