Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein oxidation has been implicated in the pathogenesis of atherosclerosis. However, the physiologically relevant pathways mediating oxidative damage have not yet been identified. Three potential mechanisms are tyrosyl radical, hydroxyl radical, and redox active metal ions. Tyrosyl radical forms o,o'-dityrosine cross-links in proteins. The highly reactive hydroxyl radical oxidizes phenylalanine residues to o-tyrosine and m-tyrosine. Metal ions oxidize low density lipoprotein (LDL) by poorly understood pathways. To explore the involvement of tyrosyl radical, hydroxyl radical, and metal ions in atherosclerosis, we developed a highly sensitive and quantitative method for measuring levels of o, o'-dityrosine, o-tyrosine, and m-tyrosine in proteins, lipoproteins, and tissue, using stable isotope dilution gas chromatography-mass spectrometry. We showed that o,o'-dityrosine was selectively produced in LDL oxidized with tyrosyl radical. Both o-tyrosine and o, o'-dityrosine were major products when LDL was oxidized with hydroxyl radical. Only o-tyrosine was formed in LDL oxidized with copper. Similar profiles of oxidation products were observed in bovine serum albumin oxidized with the three different systems. Applying these findings to LDL isolated from human atherosclerotic lesions, we detected a 100-fold increase in o,o'-dityrosine levels compared to those in circulating LDL. In striking contrast, levels of o-tyrosine and m-tyrosine were not elevated in LDL isolated from atherosclerotic tissue. Analysis of fatty streaks revealed a similar pattern of oxidation products; compared with normal aortic tissue, there was a selective increase in o,o'-dityrosine with no change in o-tyrosine. The detection of a selective increase of o,o'-dityrosine in LDL isolated from vascular lesions is consistent with the hypothesis that oxidative damage in human atherosclerosis is mediated in part by tyrosyl radical. In contrast, these observations do not support a role for free metal ions as catalysts of LDL oxidation in the artery wall.
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PMID:Mass spectrometric quantification of markers for protein oxidation by tyrosyl radical, copper, and hydroxyl radical in low density lipoprotein isolated from human atherosclerotic plaques. 901 99

The importance of reactive nitrogen species in atherosclerosis remains poorly understood, despite the semi-quantitative evidence for the presence of 3-nitrotyrosine provided by immunohistochemical staining studies. At this time, there appear to be no data describing the prevalence of nitration relative to oxidation in atherosclerotic plaque proteins. The present study used 3-nitrotyrosine and dityrosine as markers of nitration and oxidation respectively to examine the relative abundance of each process. Substantial methodological improvements were required to overcome problems associated with sensitivity and artefactual production of 3-nitrotyrosine when quantified by GLC-MS. It was shown that careful selection of hydrolysis vessel, sample reduction and the use of the oxazolinone derivative provided sample stability and exquisite sensitivity. Using these methods, it was observed that the frequency of nitration was 92+/-15 micro mol/mol of tyrosine (0.01%). Dityrosine was present at 1.5+/-0.14 mmol/mol of tyrosine (0.30%) using HPLC/fluorescence; thus nitration accounted for approx. 3% of the tyrosine modifications measured. Given that other modifications of tyrosine are known to occur in carotid plaque proteins, the contribution of nitration to the total pool of modified tyrosine is very small. However, the possibility of metabolic processes or chemical agents modifying 3-nitrotyrosine to secondary oxidation products remains an alternative explanation for the low levels demonstrated in this study.
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PMID:Comparison of nitration and oxidation of tyrosine in advanced human carotid plaque proteins. 1239 48

Dityrosine is a fluorescent molecule formed as a result of normal posttranslational processing. In many structural proteins, dityrosine confers resistance to proteolysis and physicochemical trauma as a stabilizing crosslink. Dityrosine has also been found in oxidative/nitrative stress under a variety of conditions and biological systems. In this regard, it has been used as an important biomarker for oxidatively modified proteins during UV and gamma-irradiation, aging, and exposure to oxygen free radicals, nitrogen dioxide, peroxynitrite, and lipid hydroperoxides. Renewed interest in dityrosine and other tyrosine oxidation products as clinical indicators of oxidative modification has driven the development of important techniques for the specific analysis and quantification of these molecules. The presence of elevated levels of dityrosine in mammalian tissue and urine samples has been measured by chromatographic separation followed by mass spectrometry GC-MS and HPLC-MS/MS. Increases in dityrosine levels have been associated with pathologies such as eye cataracts, atherosclerosis, acute inflammation, and Alzheimer's disease. The continued development of, and increased accessibility to, improved mass spectrometric instrumentation will expand the capability, feasibility, and sensitivity with which specific biomarkers like dityrosine can be measured.
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PMID:Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples. 1701 3