Nitrotyrosine Causes Selective Vascular Endothelial Dysfunction and DNA Damage

Mihm, Michael J.; Liang, Jing; Bauer, John

doi:10.1097/00005344-200008000-00007

Cited by 89 publications

(60 citation statements)

References 26 publications

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“…Because NT is considered a good marker of peroxynitrite formation (21), detection of NT in hearts perfused with high glucose, but not in control hearts, is strongly suggestive for increased generation of peroxynitrite. Moreover, NT may be harmful for endothelial cells (32). The recent demonstration that the increased apoptosis of myocytes, endothelial cells, and fibroblasts in heart biopsies from diabetic patients (29) and in hearts from streptozotocininduced diabetic rats (33) is selectively associated with levels of NT found in those cells supports our finding that high glucose may produce myocardial damage and cardiac cell apoptosis through the formation of NT.…”

Section: Fig 2 Nitrotyrosine Immmunostaining In Heart Perfused Withsupporting

confidence: 84%

Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat

Quagliaro²,

et al. 2002

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This study investigated coronary perfusion pressure, nitric oxide (NO) and superoxide production, nitrotyrosine (NT) formation, and cardiac cell apoptosis in isolated hearts perfused with high glucose concentration. Coronary perfusion pressure; NO and superoxide anion generation; immunostaining for NT, inducible NO synthase (iNOS), and the constitutive type of NO synthase (NOS) eNOS; iNOS and eNOS mRNA expression by Western blot and RT-PCR; and apoptosis of cardiac cells were studied in hearts perfused for 2 h with solutions containing D-glucose at a concentration of 11.1 mmol/l (control), D-glucose at the concentration of 33.3 mmol/l (high glucose), or D-glucose (33.3 mmol/l) plus glutathione (0.3 mmol/l). Perfusion of isolated hearts in conditions of high glucose concentration caused a significant increase of coronary perfusion pressure (P < 0.001) and an increase of both NO and superoxide generation. However, superoxide production was 300% higher than baseline, whereas NO production was 40% higher (P < 0.001 for both). This effect was accompanied by the formation of NT, and an increase of iNOS expression. eNOS remained unchanged. At the end of the experiments, cardiac cell apoptosis was evident in hearts perfused with high glucose. The effects of high glucose were significantly prevented by glutathione. This study demonstrates that high glucose for 2 h is enough to increase iNOS gene expression and NO release in working rat hearts. Upregulation of iNOS and raised NO generation are accompanied by a marked concomitant increase of superoxide production, a condition favoring the production of peroxynitrite, a powerful pro-oxidant that can mediate the toxic effects of high glucose on heart by itself and/or via the formation of nitrotyrosine, as suggested by the detection of cell apoptosis.

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Section: Fig 2 Nitrotyrosine Immmunostaining In Heart Perfused Withsupporting

confidence: 84%

Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat

Quagliaro²,

et al. 2002

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“…This hypothesis is strongly supported by the recent finding that the increased apoptosis of myocytes, endothelial cells, and fibroblasts in heart biopsies from diabetic patients (33) and in hearts from streptozotocin-induced diabetic rats (34) is selectively associated with the levels of NT found in those cells. Furthermore, the demonstration that NT can induce endothelial dysfunction by itself (35) and that it is present in atherosclerotic lesions in humans and diabetic cynomolgus monkeys (23,36) is additional evidence that peroxynitrite production may be strongly involved in atherogenesis.…”

Section: Results -As Reported Inmentioning

confidence: 98%

Role of Hyperglycemia in Nitrotyrosine Postprandial Generation

et al. 2002

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OBJECTIVE -Recently, much attention has been paid to the possibility that postprandial hyperglycemia may be a cardiovascular risk factor in diabetes. Oxidative stress has been involved in the pathogenesis of diabetic complications, and increased plasma levels of nitrotyrosine, a product of peroxynitrite action, have been found in the plasma of diabetic subjects. The aim of the present study was to evaluate whether postprandial hyperglycemia is accompanied by nitrotyrosine generation and, if so, to explore a possible direct role of hyperglycemia in such a phenomenon. RESEARCH DESIGN AND METHODS-A total of 23 type 2 diabetic patients and 15 matched normal healthy subjects were recruited for this study. Two different tests were performed in diabetic patients: a standard meal preceded by regular insulin (0.15 units/kg body wt) or insulin aspart (0.15 units/kg body wt) to achieve different levels of postprandial hyperglycemia. The meal test was also performed in healthy control subjects. At 0 min and 1, 2, 4, and 6 h after each meal, blood glucose, triglyceride, and nitrotyrosine levels were measured.RESULTS -Fasting nitrotyrosine was significantly increased in diabetic patients and was further increased during both meal tests in diabetic subjects but not normal subjects. As compared with regular insulin, aspart administration significantly reduced the area under the curve of both glycemia (P Ͻ 0.04) and nitrotyrosine (P Ͻ 0.03), whereas that of triglycerides was not significantly affected by the treatment.CONCLUSIONS -This study shows a direct correlation between postprandial hyperglycemia and the production of nitrotyrosine, a marker of oxidative stress, in patients with type 2 diabetes.

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“…This hypothesis is strongly supported by the recent demonstration that increased apoptosis of myocytes, endothelial cells, and fibroblasts in heart biopsy specimens from diabetic patients 32 and in hearts from streptozotocin diabetic rats, 33 even during acute hyperglycemia, 34 is selectively associated with levels of NT found in those cells. Furthermore, evidence that NT may induce endothelial dysfunction by itself 35 and that it is present in atherosclerotic lesions in humans and in diabetic cynomolgus mokeys 36 -37 suggests that peroxynitrite production may be strongly involved in atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation

et al. 2002

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Background-Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease.Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. Methods and Results-Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone; and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations of endothelial function and nitrotyrosine during the tests. Conclusions-This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug.

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Nitrotyrosine Causes Selective Vascular Endothelial Dysfunction and DNA Damage

Cited by 89 publications

References 26 publications

Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat

Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat

Role of Hyperglycemia in Nitrotyrosine Postprandial Generation

Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation

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