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Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis.

Publication ,  Journal Article
Hodgkinson, CP; Laxton, RC; Patel, K; Ye, S
Published in: Arterioscler Thromb Vasc Biol
December 2008

OBJECTIVE: Diabetes is a major risk factor for coronary heart disease. Accumulation of advanced glycation end-products (AGEs) attributable to hyperglycemia in diabetics promotes the development of atherosclerosis. However, the underlying mechanisms remain unclear. METHODS AND RESULTS: The advanced glycation end-product of low-density-lipoprotein (AGE-LDL) induced proinflammatory cytokine production in human coronary artery endothelial cells and human- and mouse-macrophages. AGE-LDL stimulated cytokine synthesis was markedly reduced in mouse macrophages with a TLR4 loss-of-function mutation. Coimmunoprecipitation experiments indicated AGE-LDL interacts with TLR4, RAGE, and CD36. Incubation of cultured macrophages with TLR4, RAGE, or CD36 antibodies inhibited AGE-LDL stimulation of tumor necrosis factor (TNF)alpha production. A competitive binding inhibitor of TLR4 blocked AGE-LDL binding to the receptor. After transfection of a HEK293 cell system with wild-type TLR4, AGE-LDL activated a signaling pathway including p38 alpha, JNK, and ERK1 kinases and AP1, Elk1, and NF-kappaB transcription factors; the net result being increased cytokine production. These effects were absent when cells were transfected with empty plasmid. Two common polymorphisms in TLR4, D299G and T399I, reduced the response of TLR4 to lipopolysaccharide (LPS) but had no effect on AGE-LDL signaling. CONCLUSIONS: These results indicate that AGE-LDL activates a TLR4-mediated signaling pathway, thus inducing proinflammatory cytokine production. This mechanism may partly explain the increased risk of atherosclerosis observed in diabetics.

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Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

December 2008

Volume

28

Issue

12

Start / End Page

2275 / 2281

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transfection
  • Toll-Like Receptor 4
  • Serum Albumin, Bovine
  • Recombinant Proteins
  • NF-kappa B
  • Mice, Knockout
  • Mice
  • Macrophages
  • Lipoproteins, LDL
 

Citation

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Chicago
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MLA
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Hodgkinson, C. P., Laxton, R. C., Patel, K., & Ye, S. (2008). Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler Thromb Vasc Biol, 28(12), 2275–2281. https://doi.org/10.1161/ATVBAHA.108.175992
Hodgkinson, Conrad P., Ross C. Laxton, Kunal Patel, and Shu Ye. “Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis.Arterioscler Thromb Vasc Biol 28, no. 12 (December 2008): 2275–81. https://doi.org/10.1161/ATVBAHA.108.175992.
Hodgkinson CP, Laxton RC, Patel K, Ye S. Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2275–81.
Hodgkinson, Conrad P., et al. “Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis.Arterioscler Thromb Vasc Biol, vol. 28, no. 12, Dec. 2008, pp. 2275–81. Pubmed, doi:10.1161/ATVBAHA.108.175992.
Hodgkinson CP, Laxton RC, Patel K, Ye S. Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2275–2281.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

December 2008

Volume

28

Issue

12

Start / End Page

2275 / 2281

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transfection
  • Toll-Like Receptor 4
  • Serum Albumin, Bovine
  • Recombinant Proteins
  • NF-kappa B
  • Mice, Knockout
  • Mice
  • Macrophages
  • Lipoproteins, LDL