Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: A potential mechanism for the accelerated vasculopathy of diabetes

Ann Marie Schmidt, Osamu Hori, Jing Xian Chen, Jian Feng Li, Jill P. Crandall, Jinghua Zhang, Rong Cao, Shi Du Yan, Jerold Brett, David Stern

Research output: Contribution to journalArticle

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Abstract

Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell recognition protein on the endothelial cell surface (EC), has been associated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irreversible advanced glycation endproducts (AGEs), could mediate VCAM-1 expression by interacting with their endothelial cell receptor (receptor for AGE, RAGE). Exposure of cultured human ECs to AGEs induced expression of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, and was associated with increased levels of VCAM-1 transcripts. The inhibitory effect of anti-RAGE IgG, a truncated form of the receptor (soluble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE-RAGE-induced oxidant stress was central to VCAM-1 induction. Electrophoretic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-kB in the VCAM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma. These data are consistent with the hypothesis that AGE-RAGE interaction induces expression of VCAM-1 which can prime diabetic vasculature for enhanced interaction with circulating monocytes.

Original languageEnglish (US)
Pages (from-to)1395-1403
Number of pages9
JournalJournal of Clinical Investigation
Volume96
Issue number3
StatePublished - Sep 1995
Externally publishedYes

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Vascular Cell Adhesion Molecule-1
Endothelial Cells
IgG Receptors
Acetylcysteine
NF-kappa B
Electrophoretic Mobility Shift Assay
Vascular Diseases
Oxidants
Advanced Glycosylation End Product-Specific Receptor
Monocytes
Atherosclerosis
Rabbits
Antigens

Keywords

  • Adhesion molecule
  • Atherosclerosis
  • Endothelium
  • Hyperglycemia
  • Oxidation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice : A potential mechanism for the accelerated vasculopathy of diabetes. / Schmidt, Ann Marie; Hori, Osamu; Chen, Jing Xian; Li, Jian Feng; Crandall, Jill P.; Zhang, Jinghua; Cao, Rong; Yan, Shi Du; Brett, Jerold; Stern, David.

In: Journal of Clinical Investigation, Vol. 96, No. 3, 09.1995, p. 1395-1403.

Research output: Contribution to journalArticle

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abstract = "Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell recognition protein on the endothelial cell surface (EC), has been associated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irreversible advanced glycation endproducts (AGEs), could mediate VCAM-1 expression by interacting with their endothelial cell receptor (receptor for AGE, RAGE). Exposure of cultured human ECs to AGEs induced expression of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, and was associated with increased levels of VCAM-1 transcripts. The inhibitory effect of anti-RAGE IgG, a truncated form of the receptor (soluble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE-RAGE-induced oxidant stress was central to VCAM-1 induction. Electrophoretic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-kB in the VCAM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma. These data are consistent with the hypothesis that AGE-RAGE interaction induces expression of VCAM-1 which can prime diabetic vasculature for enhanced interaction with circulating monocytes.",
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