Mass spectrometric quantification of amino acid oxidation products identifies oxidative mechanisms of diabetic end-organ damage - PubMed (original) (raw)

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Mass spectrometric quantification of amino acid oxidation products identifies oxidative mechanisms of diabetic end-organ damage

Anuradha Vivekanadan-Giri et al. Rev Endocr Metab Disord. 2008 Dec.

Abstract

Diabetes mellitus is increasingly prevalent worldwide. Diabetic individuals are at markedly increased risk for premature death due to cardiovascular disease. Furthermore, substantial morbidity results from microvascular complications which include retinopathy, nephropathy, and neuropathy. Clinical studies involving diabetic patients have suggested that degree of diabetic hyperglycemia correlates with risk of complications. Recent evidence implicates a central role for oxidative stress and vascular inflammation in all forms of insulin resistance, obesity, diabetes and its complications. Although, glucose promotes glycoxidation reactions in vitro and products of glycoxidation and lipoxidation are elevated in plasma and tissue in diabetics, the exact relationships among hyperglycemia, the diabetic state, and oxidative stress are not well-understood. Using a combination of in vitro and in vivo experiments, we have identified amino acid oxidation markers that serve as molecular fingerprints of specific oxidative pathways. Quantification of these products utilizing highly sensitive and specific gas chromatography/mass spectrometry in animal models of diabetic complications and in humans has provided insights in oxidative pathways that result in diabetic complications. Our studies strongly support the hypothesis that unique oxidants are generated in the microenvironment of tissues vulnerable to diabetic damage. Potential therapies interrupting these reactive pathways in target tissue are likely to be beneficial in preventing diabetic complications.

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Figures

Fig. 1

Fig. 1

Oxidative stress pathways in diabetic complications. AGE advanced glycosylation end-products, ALE advanced lipoxidation end-products, eNOS endothelial nitric oxide synthase, HOCl hypochlorous acid, MPO myeloperoxidase, _NO_• nitric oxide, NOX NAD(P)H oxidase, PUFA polyunsaturated fatty acid, XO xanthine oxidase. Modified from [26]

Fig. 2

Fig. 2

Quantification of _ortho_-tyrosine (a), _meta_-tyrosine (b), _o,o′_-dityrosine (c), and 3-nitrotyrosine (d) in aortic proteins isolated from control and diabetic Cynomolgus monkeys. Aortic tissue was harvested from control and diabetic animals at the end of the 6-month study. Tissue was delipidated, hydrolyzed, and amino acids were quantified by GC/MS. *p<0.01 by Student's _t_-test. Reproduced from [29]

Fig. 3

Fig. 3

Quantification of oxidized amino acids and lipids in retinal tissue isolated from control and hyperglycemic Sprague–Dawley rats. Rats were rendered hyperglycemic with STZ. At the end of the 6-week study, retinal tissue was harvested from the animals. The isolated amino acids were derivatized and analyzed by GC/MS with selected ion monitoring (a and b). HODEs (hydroxyoctadecadienoic acid) were quantified by reversed-phase HPLC (c). *p<0.05 by analysis of variance. Reproduced from [28]

Fig. 4

Fig. 4

Correlation of _ortho_-tyrosine, _meta_-tyrosine _o,o′_-dityrosine, or 3-nitrotyrosine with HODEs in retinal tissue of control and diabetic Sprague–Dawley rats. At the end of the 6-week study, retinal tissue harvested from control animals, control animals treated with aminoguanidine, diabetic animals, and diabetic animals treated with aminoguanidine was analyzed for oxidation products. Lines represent the linear least-squares fit of the data. Reproduced from [28]

Fig. 5

Fig. 5

MPO generates chlorinated and nitrated HDL in human plasma in subjects with CAD. Levels of MPO-oxidized amino acids were determined in HDL isolated from healthy subjects and subjects with CAD. a 3-chlorotyrosine and b 3-nitrotyrosine. Linear regression analysis demonstrated a strong correlation between levels of 3-chlorotyrosine and levels of 3-nitrotyrosine (c) in plasma HDL consistent with similar pathway of generation of both these markers. Reproduced from [50, 60]

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