AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease.
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, N(epsilon)-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-F(2) 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-kappaB p65 nuclear translocation in response to MG and N(epsilon)-carboxymethyl-lysine. These events involved epidermal growth factor receptor-dependent PKC-delta redox-sensitive Tyr-311 and Tyr-332 phosphorylation and were suppressed in AGER1(+) ECs and enhanced in sh-mRNA-AGER1(+) ECs. Aortic ROS, PKC-delta 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.
Cai
Weijing
W
Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, Box 1640, One Gustave Levy Place, New York, NY 10029, USA.
Torreggiani
Massimo
M
Zhu
Li
L
Chen
Xue
X
He
John Cijiang
JC
Striker
Gary E
GE
Vlassara
Helen
H
D021581:Active Transport, Cell Nucleus; D000367:Age Factors; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000201:enzymology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014652:Vascular Diseases / Q000201:enzymology / Q000517:prevention & control*
D017127:Glycation End Products, Advanced; D008562:Membrane Glycoproteins; D021122:Protein Subunits; C498143:RELA protein, human; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D009249:NADP; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C497259:Prkcd protein, mouse; C512478:EGFR protein, human; D066246:ErbB Receptors; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D008239:Lysine