Placental protein tyrosine nitration and MAPK in type 1 diabetic pre-eclampsia: Impact of antioxidant vitamin supplementation

Johnston, Pete; Powell, Lesley; McCance, David R.; Pogue, Kathy M.; McMaster, Cyril; Gilchrist, Sarah; Holmes, Valerie; McGinty, Ann

doi:10.1016/j.jdiacomp.2013.02.001

Cited by 9 publications

(8 citation statements)

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“…Increased placental protein tyrosine nitration was documented in diabetic patients [63] and, in animal models of diabetes, 3NT was shown to be enhanced in the kidney [64] and in the ventricle and lens [65]. Similarly, 3NT is upregulated in diabetic cardiomyopathy [66].…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells

Qadri

et al. 2013

Cardiovasc Diabetol

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BackgroundIncreased levels of the sugar metabolite methylglyoxal (MG) in vivo were shown to participate in the pathophysiology of vascular complications in diabetes. Alterations of endothelial nitric oxide synthase (eNOS) activity by hypophosphorylation of the enzyme and enhanced monomerization are found in the diabetic milieu, and the regulation of this still remains undefined. Using various pharmacological approaches, we elucidate putative mechanisms by which MG modulates eNOS-associated functions of MG-stimulated superoxide normalO2•- production, phosphorylation status and eNOS uncoupling in EA.hy926 human endothelial cells.MethodsIn cultured EA.hy926 endothelial cells, the effects of MG treatment, tetrahydrobiopterin (BH4; 100 μM) and sepiapterin (20 μM) supplementation, NOS inhibition by NG-nitro-L-arginine methyl ester (L-NAME; 50 μM), and inhibition of peroxynitrite (ONOO-) formation (300 μM Tempol plus 50 μM L-NAME) on eNOS dimer/monomer ratios, Ser-1177 eNOS phosphorylation and 3-nitrotyrosine (3NT) abundance were quantified using immunoblotting. O2•-–dependent fluorescence was determined using a commercially available kit and tissue biopterin levels were measured by fluorometric HPLC analysis.ResultsIn EA.hy926 cells, MG treatment significantly enhanced O2•- generation and 3NT expression and reduced Ser-1177 eNOS phosphorylation, eNOS dimer/monomer ratio and cellular biopterin levels indicative of eNOS uncoupling. These effects were significantly mitigated by administration of BH4, sepiapterin and suppression of ONOO- formation. L-NAME treatment significantly blunted eNOS-derived O2•- generation but did not modify eNOS phosphorylation or monomerization.ConclusionMG triggers eNOS uncoupling and hypophosphorylation in EA.hy926 endothelial cells associated with O2•- generation and biopterin depletion. The observed effects of the glycolysis metabolite MG presumably account, at least in part, for endothelial dysfunction in diabetes.

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Section: Discussionmentioning

confidence: 99%

Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells

Qadri

et al. 2013

Cardiovasc Diabetol

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“…May exist several cellular sources of superoxide in the placenta, which includes the mitochondrial electron transport chain, xanthine oxidase, and also the NADPH oxidase specifically in syncytiotrophoblast, vascular endothelium, and stromal cells. 72 Increased levels of nitrated proteins and nitrotyrosine residues have been reported in placental tissue of pregnancies complicated by pre-eclampsia, [73][74][75] and it could reveal an excess lipid peroxidation and oxidation of structural proteins and enzymes, which is coherent with the finding of conjugated dienes and 4-hydroxynonenal -lysine adducts in pre-eclamptic villous tissue but not in healthy placenta. 74 Thus, the data strongly suggest that nitrative stress and covalent modification of protein function may affect placental function.…”

Section: Discussionmentioning

confidence: 80%

Role of aspirin‐triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre‐eclampsia

Gil-Villa

Alvarez

Velásquez-Berrío

et al. 2019

American J Rep Immunol

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Problem:Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirintriggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. Method of study:Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated.Results: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. Conclusion:Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia. K E Y W O R D Sacetylsalicylic acid, aspirin-triggered lipoxins, inflammation, oxidative stress, pre-eclampsia, salicylic acid

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“…The DAPIT inclusion and exclusion criteria as well as maternal serum HbA1c, PAI-1 and PAI-II as well as cord Vitamin C and E analyses and placental nitrotyrosine and vitamin C and E has been described previously [13,17]. Microplate Reader with data expressed as µmol/mg.…”

Section: Subjectsmentioning

confidence: 99%

“…The hyperglycaemic milieu in diabetic pregnancy resulting in inherent oxidative stress has been observed in uncomplicated normotensive T1DM pregnancy as demonstrated by placental nitrotyrosine immunopositivity reflecting the pro-oxidant peroxynitrite production [17].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…In view of the fact that the initiation of vitamin supplementation varied between 8 and 22 weeks of gestation, vitamin supplemented subjects were categorised according to whether supplementation began in week 8-12 or week[13][14][15][16][17][18][19][20][21][22]. No significant differences in the various outcome measures were found between these sub-groups, indicating that the gestational point at which vitamin supplementation began did not impact on antioxidant enzyme status or lipid peroxidation markers (data not shown).…”

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confidence: 99%

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Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: The effect of vitamin C and E supplementation

Johnston

McCance

Holmes

et al. 2016

Journal of Diabetes and its Complications

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Placental protein tyrosine nitration and MAPK in type 1 diabetic pre-eclampsia: Impact of antioxidant vitamin supplementation

Cited by 9 publications

References 35 publications

Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells

Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells

Role of aspirin‐triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre‐eclampsia

Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: The effect of vitamin C and E supplementation

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