Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

Tannous, Marie; Rabini, R. A.; Vignini, Arianna; Moretti, Natalia; Fumelli, P.; Zielinski, Barbara S.; Mazzanti, Laura; Mutus, Bülent

doi:10.1007/s001250051192

Cited by 94 publications

(56 citation statements)

References 21 publications

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“…The possibility that high glucose induces iNOS overexpression has already been reported in platelets (where this phenomenon is accompanied by increased peroxynitrite production) (34) streptozotocin-diabetic rats (35). Although O 2 Ϫ production in hearts perfused with high glucose was scavenged by glutathione treatment, iNOS mRNA and protein expression were not affected.…”

Section: Fig 2 Nitrotyrosine Immmunostaining In Heart Perfused Withmentioning

confidence: 82%

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 Withmentioning

confidence: 82%

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

Quagliaro²,

et al. 2002

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“…We do not know if this is related to the decrease in some macrophage functions, as demonstrated by the decreased release of cytokines. Several reports indicate upregulation of the iNOS pathway in the diabetic state (44,45). Nitrite/nitrate accumulation in wound fluid of streptozotocin-treated rats was significantly diminished (46).…”

Section: Discussionmentioning

confidence: 97%

Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice.

et al. 2000

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Macrophage dysfunction is a likely mechanism underlying common diabetic complications such as increased susceptibility to infection, accelerated atherosclerosis, and disturbed wound healing. There are no available studies on the function of tissue macrophages in diabetes in humans. We have therefore studied peritoneal macrophages from diabetic type 2-like db/db mice. We found that the release of tumor necrosis factor-␣ and interleukin-1␤ from lipopolysaccharide plus interferon-␥-stimulated macrophages and vascular endothelial growth factor from both stimulated and nonstimulated macrophages was significantly reduced in diabetic animals compared with nondiabetic controls. Nitric oxide production from the stimulated db/db macrophages was significantly higher than that in the db/+ cultures, whereas there was no difference in their ability to generate reactive oxygen species. When studied both at light and electron microscopic levels, macrophages in diabetic animals had an altered morphological appearance compared with those of normal controls. We conclude that the function and morphology of the macrophages are disturbed in db/db mice and that this disturbance is related to the mechanisms underlying common inflammatory and degenerative manifestations in diabetes.

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“…Thus, nitrotyrosine is now generally considered a collective index of reactive nitrogen species, rather than a specific indicator of peroxynitrite formation [68,69]. The possibility that diabetes is associated with increased nitrosative stress is supported by the recent detection of increased nitrotyrosine plasma levels in type 2 diabetic patients [8] and iNOSdependent peroxynitrite production in diabetic platelets [15]. Nitrotyrosine formation is detected in the artery wall of monkeys during hyperglycemia [70] and in diabetic patients during an increase of postprandial hyperglycemia [10,11].…”

Section: The Role Of Oxidative and Nitrosative Stress In The Pathogenmentioning

confidence: 99%

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

Pacher

Obrosova

Mabley

et al. 2005

CMC

306

243

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Macro-and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.

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Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

Cited by 94 publications

References 21 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

Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice.

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

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