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AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular

Weijing Cai1, Massimo Torreggiani, Li Zhu

  • 1Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, Box 1640, One Gustave Levy Place, New York, NY 10029, USA.

American Journal of Physiology. Cell Physiology
|December 4, 2009
PubMed

Insights

Advanced glycated end-product receptor 1 (AGER1) prevents vascular damage by inhibiting reactive oxygen species (ROS). This study clarifies how specific advanced glycated end products (AGEs) trigger ROS via NADPH oxidase, with AGER1 offering protection.

Area of Science:

  • Molecular Biology
  • Vascular Biology
  • Oxidative Stress Research

Background:

  • Advanced glycated end-product receptor 1 (AGER1) is known to protect against vascular disease by inhibiting reactive oxygen species (ROS).
  • The precise advanced glycated end products (AGEs), their sources, and the specific pathways through which they promote ROS generation remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism of NADPH oxidase (NOX)-dependent ROS generation induced by specific AGEs (N(epsilon)-carboxymethyl-lysine and methylglyoxal-modified BSA).
  • To investigate the role of AGER1 in modulating AGE-induced ROS production in human aortic endothelial cells and in vivo mouse models.

Main Methods:

  • Assessed NOX activity, superoxide anion production, and NF-kappaB p65 nuclear translocation in AGER1-overexpressing and AGER1-knockdown endothelial cells exposed to defined AGEs.
  • Utilized human aortic endothelial cells (EC), ECV304 cells, and aortic segments from aged mice on low-AGE or AGE-supplemented diets.
  • Examined epidermal growth factor receptor (EGFR)-dependent PKC-delta phosphorylation at Tyr-311 and Tyr-332.

Main Results:

  • Wild-type and AGER1-knockdown cells, but not AGER1-overexpressing cells, exhibited increased NOX activity, superoxide anions, and NF-kappaB p65 translocation in response to AGEs.
  • AGE-induced ROS generation involved EGFR-dependent, redox-sensitive phosphorylation of PKC-delta, which was suppressed by AGER1 overexpression and enhanced by AGER1 knockdown.
  • Aged mice on an AGE-supplemented diet showed significantly elevated aortic ROS, PKC-delta phosphorylation, NOX expression, and nuclear p65 compared to controls, with lower AGER1 levels.

Conclusions:

  • Circulating AGEs stimulate NADPH-dependent ROS generation, contributing to vascular aging through pathways involving NOX activation and PKC-delta signaling.
  • AGER1 plays a crucial protective role by suppressing AGE-induced ROS generation, highlighting its potential as a therapeutic target in vascular diseases associated with oxidative stress.

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