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Open AccessArticle

High Glucose-Mediated Tyrosine Nitration of PI3-Kinase: A Molecular Switch of Survival and Apoptosis in Endothelial Cells

Retinopathy Research, Augusta Biomedical Research Corporation Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
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Author to whom correspondence should be addressed.
Currently at Determent of Pharmacology& Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia Governorate 35516, Egypt.
Antioxidants 2018, 7(4), 47; https://doi.org/10.3390/antiox7040047
Received: 21 February 2018 / Revised: 19 March 2018 / Accepted: 21 March 2018 / Published: 25 March 2018
(This article belongs to the Special Issue Oxidative Stress and Cardiovascular Disease)
Diabetes and hyperglycemia are associated with increased retinal oxidative and nitrative stress and vascular cell death. Paradoxically, high glucose stimulates expression of survival and angiogenic growth factors. Therefore, we examined the hypothesis that high glucose-mediated tyrosine nitration causes inhibition of the survival protein PI3-kinase, and in particular, its regulatory p85 subunit in retinal endothelial cell (EC) cultures. Retinal EC were cultured in high glucose (HG, 25 mM) for 3 days or peroxynitrite (PN, 100 µM) overnight in the presence or absence of a peroxynitrite decomposition catalyst (FeTPPs, 2.5 µM), or the selective nitration inhibitor epicatechin (100 µM). Apoptosis of ECs was assessed using TUNEL assay and caspase-3 activity. Immunoprecipitation and Western blot were used to assess protein expression and tyrosine nitration of p85 subunit and its interaction with the p110 subunit. HG or PN accelerated apoptosis of retinal ECs compared to normal glucose (NG, 5 mM) controls. HG- or PN-treated cells also showed significant increases in tyrosine nitration on the p85 subunit of PI3-kinase that inhibited its association with the catalytic p110 subunit and impaired PI3-kinase/Akt kinase activity. Decomposing peroxynitrite or blocking tyrosine nitration of p85 restored the activity of PI3-kinase, and prevented apoptosis and activation of p38 MAPK. Inhibiting p38 MAPK or overexpression of the constitutively activated Myr-Akt construct prevented HG- or peroxynitrite-mediated apoptosis. In conclusion, HG impairs pro-survival signals and causes accelerated EC apoptosis, at least in part via tyrosine nitration and inhibition of PI3-kinase. Inhibitors of nitration can be used in adjuvant therapy to delay diabetic retinopathy and microvascular complication. View Full-Text
Keywords: peroxynitrite; tyrosine nitration; high glucose; PI3-kinase; apoptosis; endothelial cells; p38 MAPK; survival; Akt peroxynitrite; tyrosine nitration; high glucose; PI3-kinase; apoptosis; endothelial cells; p38 MAPK; survival; Akt
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Elshaer, S.L.; Lemtalsi, T.; El-Remessy, A.B. High Glucose-Mediated Tyrosine Nitration of PI3-Kinase: A Molecular Switch of Survival and Apoptosis in Endothelial Cells. Antioxidants 2018, 7, 47.

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