Epicatechin Selectively Prevents Nitration but Not Oxidation Reactions of Peroxynitrite

Schröeder, Peter; Klotz, Lars‐Oliver; Buchczyk, Darius P.; Sadik, Christian D.; Schewe, Tankred; Sies, Helmut

doi:10.1006/bbrc.2001.5210

Cited by 80 publications

(47 citation statements)

References 28 publications

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“…Ferroxidase activities were also measured in the presence of reduced glutathione (GSH, 850 μmol/L, Acros Organic, Thermo-Fisher Scientific) or (-)-epicatechin (50 μmol/L; Sigma-Aldrich Chemical Co), a flavanol known for its ability to protect against nitration but not from oxidation induced by peroxynitrite. 24 GSH and (-)-epicatechin at these concentrations, in previous in vitro experiments, induced similar reductions in nitration of free tyrosine after peroxynitrite exposure. Standard solutions of (-)-epicatechin were prepared in dimethyl sulfoxide and stored at −20°C: after dilution, the final concentration of dimethyl sulfoxide was 0.01%.…”

Section: Peroxynitrite Synthesis and Ex Vivo Experiments On Ceruloplasupporting

confidence: 73%

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

Cabassi

Binno

Tedeschi

et al. 2014

Circulation Research

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Rationale: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification. Objective: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI. Methods and Results: In patients with chronic HF (n=96, 76±9 years; New York Heart Association class, 2.9±0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (−20%) and inversely related to nitrotyrosine-bound ceruloplasmin ( r , −0.305; P =0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29–6.75]; P =0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(−)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop. Conclusions: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition.

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Section: Peroxynitrite Synthesis and Ex Vivo Experiments On Ceruloplasupporting

confidence: 73%

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

Cabassi

Binno

Tedeschi

et al. 2014

Circulation Research

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“…These increases in tyrosine nitration were blocked by the specific peroxynitrite decomposition catalyst FeTTPs (2.5 µM) and by the specific nitration inhibitor epicatechin (100 µM). Epicatechin, a dietary flavanol, has been used to selectively block the nitrating effect of peroxynitrite on tyrosine residues (Schroeder et al, 2001; Immunoprecipitation with p85 subunit of PI 3-kinase and western blot analysis using antinitrotyrosine antibody showed that cells treated with high glucose (HG) or peroxynitrite (PN) had significantly more nitration on the regulatory p85 subunit compared with cells cultured in normal glucose (NG). (*P<0.05 compared to NG.)…”

Section: R E T R a C T E Dmentioning

confidence: 99%

Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration

El-Remessy

Bartoli

Platt

et al. 2005

Journal of Cell Science

127

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In diabetic retinopathy, endothelial cell apoptosis is paradoxically increased despite upregulation of the potent pro-survival factor VEGF. We tested the hypothesis that elevated glucose levels disrupt VEGF's pro-survival function via peroxynitrite-mediated alteration of the Akt-1/p38 MAP kinase signaling pathway by studies of retinal endothelial cells in vitro. High glucose or exogenous peroxynitrite caused significant increases in apoptosis in the presence or absence of VEGF. Treatment with a peroxynitrite decomposition catalyst blocked these effects, implying a causal role of peroxynitrite. Peroxynitrite or high glucose treatment also increased phosphorylation of p38 MAP kinase, whereas phosphorylation of Akt-1 was significantly decreased in basal or VEGF-stimulated conditions. High glucose- or peroxynitrite-treated cells also showed significant increases in tyrosine nitration on the p85 subunit of PI 3-kinase that blocked PI 3-kinase and Akt-1 kinase activity. Inhibiting peroxynitrite formation or blocking tyrosine nitration of p85 restored the activity of PI 3-kinase and Akt-1 kinase, blocked phosphorylation of p38 MAP kinase and normalized pro-survival function. Transfecting the cells with constitutively active Akt-1 or inhibiting activity of p38 MAP kinase completely masked the pro-apoptotic effects of high glucose and exogenous peroxynitrite, suggesting an interaction between the Akt-1 and p38 MAP kinase pathways. In conclusion, high glucose treatment blocks the pro-survival effect of VEGF and causes accelerated endothelial cell apoptosis via the action of peroxynitrite in causing tyrosine nitration of PI 3-kinase, inhibiting activity of Akt-1 kinase and increasing the activity of p38 MAP kinase.

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“…Figure 4 is a representative Western blot demonstrating that peroxynitrite induces tyrosine nitration of the 100-kDa ␣-subunit, 50-kDa ␤-subunit, and 15-kDa FXYD subunit (lanes [1][2][3][4][5]. It has been reported that the flavonoid epicatechin selectively prevents nitration but not other peroxynitrite-induced oxidative reactions (19). We confirmed that 100 or 25 M epicatechin prevents peroxynitrite-induced tyrosine nitration, even at the highest concentration (750 M) of peroxynitrite (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To test whether tyrosine nitration was the sole reason for inhibition of ATPase activity, we used epicatechin. Epicatechin is a polyphenol flavonoid found in dark chocolate, green tea, and red wine and is a reported selective inhibitor of nitration but not other peroxynitrite-induced oxidation reactions (19). Schroeder et al (19) hypothesized that the selectivity of epicatechin is a result of its ability to scavenge the tyrosyl radical, a peroxynitrite intermediate, rather than directly scavenge peroxynitrite.…”

Section: Discussionmentioning

confidence: 99%

The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity

Reifenberger¹,

Arnett²,

Gatto³

et al. 2008

American Journal of Physiology-Renal Physiology

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Reifenberger MS, Arnett KL, Gatto C, Milanick MA. The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity. Am J Physiol Renal Physiol 295: F1191-F1198, 2008. First published August 13, 2008; doi:10.1152/ajprenal.90296.2008Peroxynitrite is a reactive nitrogen species produced when nitric oxide and superoxide react. In vivo studies suggest that reactive oxygen species and, perhaps, peroxynitrite can influence Na-K-ATPase function. However, the direct effects of peroxynitrite on Na-K-ATPase function remain unknown. We show that a single bolus addition of peroxynitrite inhibited purified renal Na-K-ATPase activity, with IC 50 of 107 Ϯ 9 M. To mimic cellular/physiological production of peroxynitrite, a syringe pump was used to slowly release (ϳ0.85 M/s) peroxynitrite. The inhibition of Na-K-ATPase activity induced by this treatment was similar to that induced by a single bolus addition of equal cumulative concentration. Peroxynitrite produced 3-nitrotyrosine residues on the ␣, ␤, and FXYD subunits of the Na pump. Interestingly, the flavonoid epicatechin, which prevented tyrosine nitration, was unable to blunt peroxynitrite-induced ATPase inhibition, suggesting that tyrosine nitration is not required for inhibition. Peroxynitrite led to a decrease in iodoacetamidofluorescein labeling, implying that cysteine modifications were induced. Glutathione was unable to reverse ATPase inhibition. The presence of Na ϩ and low MgATP during peroxynitrite treatment increased the IC 50 to 145 Ϯ 10 M, while the presence of K ϩ and low MgATP increased the IC50 to 255 Ϯ 13 M. This result suggests that the EPNa conformation of the pump is slightly more sensitive to peroxynitrite than the E(K) conformation. Taken together, these results show that peroxynitrite is a potent inhibitor of Na-K-ATPase activity and that peroxynitrite can induce amino acid modifications to the pump. P-type ATPase; reactive oxygen species; nitrotyrosine; nitric oxide THE CONTRIBUTION OF ELEVATED production of reactive oxygen and nitrogen species (ROS and RNS, respectively) to cell dysfunction in a variety of disease states via induction of oxidative damage to cell macromolecules, such as lipids, DNA, and proteins, is increasingly recognized (1, 17). Peroxynitrite is a damaging RNS that is produced in vivo when nitric oxide (NO) and superoxide react (for review see Refs. 17 and 21). The reaction rate between NO and superoxide is nearly diffusion limited; it is three-to fourfold higher than the reaction rate between superoxide and SOD (17, 18) when superoxide is less than its K m . Thus, even if the NO concentration is as low as the SOD concentration, peroxynitrite is likely to form, even in the presence of SOD.Peroxynitrite has a short (Ͻ1-s) half-life. It can react with tyrosine residues, generating 3-nitrotyrosine, which is stable. 3-Nitrotyrosine levels are elevated in a number of conditions, including cardiovascular diseases, hyperglycemia, and renal ischemia-reperfusion injuries (17, 25).The effect of peroxynitrite on ...

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Epicatechin Selectively Prevents Nitration but Not Oxidation Reactions of Peroxynitrite

Cited by 80 publications

References 28 publications

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration

The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity

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