Next Article in Journal
Characterization of Phenolic Compounds in Wine Lees
Next Article in Special Issue
Interplay between Oxidative Stress and Platelet Activation in Coronary Thrombus of STEMI Patients
Previous Article in Journal
Polymeric Nanoparticles for Increasing Oral Bioavailability of Curcumin
Article Menu
Issue 4 (April) cover image

Export Article

Open AccessArticle
Antioxidants 2018, 7(4), 47; https://doi.org/10.3390/antiox7040047

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
Currently at Determent of Pharmacology& Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia Governorate 35516, Egypt.
*
Author to whom correspondence should be addressed.
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)
Full-Text   |   PDF [7842 KB, uploaded 3 May 2018]   |  

Abstract

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
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Antioxidants EISSN 2076-3921 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top