AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-δ: implications for vascular disease
Open Access
- 1 March 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 298 (3), C624-C634
- https://doi.org/10.1152/ajpcell.00463.2009
Abstract
Advanced glycated end-product receptor 1 (AGER1) protects against vascular disease promoted by oxidants, such as advanced glycated end products (AGEs), via inhibition of reactive oxygen species (ROS). However, the specific AGEs, sources, and pathways involved remain undefined. The mechanism of cellular NADPH oxidase (NOX)-dependent ROS generation by defined AGEs, Nε-carboxymethyl-lysine- and methylglyoxal (MG)-modified BSA, was assessed in AGER1 overexpressing (AGER1+ EC) or knockdown (sh-mRNA-AGER1+ EC) human aortic endothelial (EC) and ECV304 cells, and aortic segments from old (18 mo) C57BL6-F2 mice, propagated on low-AGE diet (LAGE), or LAGE supplemented with MG (LAGE+MG). Wild-type EC and sh-mRNA-AGER1+ EC, but not AGER1+ EC, had high NOX p47 phox and gp91 phox activity, superoxide anions, and NF-κB p65 nuclear translocation in response to MG and Nε-carboxymethyl-lysine. These events involved epidermal growth factor receptor-dependent PKC-δ redox-sensitive Tyr-311 and Tyr-332 phosphorylation and were suppressed in AGER1+ ECs and enhanced in sh-mRNA-AGER1+ ECs. Aortic ROS, PKC-δ Tyr-311, and Tyr-332 phosphorylation, NOX expression, and nuclear p65 in older LAGE+MG mice were significantly increased above that in age-matched LAGE mice, which had higher levels of AGER1. In conclusion, circulating AGEs induce NADPH-dependent ROS generation in vascular aging in both in vitro and in vivo models. Furthermore, AGER1 provides protection against AGE-induced ROS generation via NADPH.Keywords
This publication has 76 references indexed in Scilit:
- Reactive oxygen species: Destroyers or messengers?Biochemical Pharmacology, 2009
- RAGE-Induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in DiabetesJournal of the American Society of Nephrology, 2009
- In Skeletal Muscle Advanced Glycation End Products (AGEs) Inhibit Insulin Action and Induce the Formation of Multimolecular Complexes Including the Receptor for AGEsJournal of Biological Chemistry, 2008
- Apocynin: Molecular AptitudesMediators of Inflammation, 2008
- Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic MiceArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- AGE/RAGE produces endothelial dysfunction in coronary arterioles in Type 2 diabetic miceAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- Endothelial Dysfunction in Patients with Chronic Kidney Disease Results from Advanced Glycation End Products (AGE)-Mediated Inhibition of Endothelial Nitric Oxide Synthase through RAGE ActivationClinical Journal of the American Society of Nephrology, 2008
- Activation of NADPH oxidase by transforming growth factor-β in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-κB-dependent mechanismBiochemical Journal, 2007
- Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significanceOncogene, 2006
- Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptorProceedings of the National Academy of Sciences of the United States of America, 2006