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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hodgkinson, CP; Laxton, RC; Patel, K; Ye, S

Published Date

  • December 2008

Published In

Volume / Issue

  • 28 / 12

Start / End Page

  • 2275 - 2281

PubMed ID

  • 18818414

Pubmed Central ID

  • 18818414

Electronic International Standard Serial Number (EISSN)

  • 1524-4636

Digital Object Identifier (DOI)

  • 10.1161/ATVBAHA.108.175992

Language

  • eng

Conference Location

  • United States