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Cited by 513Advanced Glycation End Products researchNitric Oxide and Endothelin EffectsAldose Reductase and Taurine

Glycation, Inflammation, and RAGE: A Scaffold for the Macrovascular Complications of Diabetes and Beyond

Yan, Shi Fang, Ramasamy, Ravichandran, Naka, Yoshifumi, Schmidt, Ann Marie·2003·Circulation Research
DOI 10.1161/01.res.0000103862.26506.3d
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Abstract

The cardiovascular complications of diabetes represent the leading cause of morbidity and mortality in affected subjects. The impact of hyperglycemia may be both direct and indirect: indirect consequences of elevated blood glucose lead to generation of advanced glycation endproducts, the products of nonenzymatic glycation/oxidation of proteins/lipids that accumulate in the vessel wall, and are signal transduction ligands for Receptor for AGE (RAGE). Although enhanced in diabetes, AGE accumulation also occurs in euglycemia and aging, albeit to lower degrees, driven by oxidant stress and inflammation. In hyperglycemia, production of 3-deoxyglucosone, at least in part via the polyol pathway, provides an amplification loop to sustain AGE generation, oxidant stress, and vascular activation. Furthermore, recruitment of inflammatory cells bearing S100/calgranulins, also ligands for RAGE, augments vascular dysfunction. We hypothesize that activation of RAGE is a final common pathway that transduces signals from these diverse biochemical and molecular species, leading to cardiovascular perturbation. Ultimately, these pathways synergize to construct a scaffold on which the complications of diabetes in the vasculature and heart may be built. We propose that antagonism of RAGE will provide a unique means to dismantle this scaffold and, thereby, suppress initiation/progression of vascular disease and cardiac dysfunction that accompany diabetes and aging.

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  • Inflammatory signals such as LPS, pro-inflammatory cytokines, reactive oxygen species, advanced glycation end products, and oxidized LDL cause IKKβ phosphorylation; this phosphorylates IκBα, leading to its ubiquitination and degradation, which releases NF-κB to enter the nucleus and induce pro-inflammatory genes.

    “Extracellular inflammatory signals including lipopolysaccharide (LPS), pro-inflammatory cytokines, reactive oxygen species, advanced glycation end products, and oxidized low-density lipoprotein trigger the phosphorylation of IKKβ, which in turn phosphorylates IκBα for ubiquitination and degradation by proteasome [13–18].”

    From Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-κB pathway in macrophages and splenocytes (2013) · cites this paper as [17]

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Research works printed but not linked: 19

  1. [12]12. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Yan SD, Hofmann M, Yan SF, Pischetsrider M, Stern D, Schmidt AM. N 𝛜 (carboxymethyl)lysine modifications of proteins are ligands for RAGE that activate cell signaling pathways and modulate gene expression. J Biol Chem . 1999; 274:31740-31749.
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  13. [58]58. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen J, Nagashima M, Nitecki D, Morser J, Stern D, Schmidt AM. RAGE is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system. J Biol Chem . 1995;270:25752-25761.
  14. [70]70. Lander HL, Tauras JM, Ogiste JS, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation endproducts triggers a MAP kinase pathway regulated by oxidant stress. J Biol Chem . 1997;272: 17810-17814.
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  17. [92]92. Sakaguchi T, Yan SF, Yan SD, Rong LL, Sousa M, Belov D, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y. Arterial restenosis: central role of RAGEdependent neointimal expansion. J Clin Invest . 2003;111:959-972.
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Authors
Yan, S. F., Ramasamy, R., Naka, Y., & Schmidt, A. M.
Affiliations
Columbia University Irving Medical Center (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2003-12-12
Volume
93
Issue
12
Pages
1159-1169
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.0000103862.26506.3d
OpenAlex
W2157441872
Cited by
513
References
127
Citations by year
2026: 15 · 2025: 12 · 2024: 15 · 2023: 18 · 2022: 19 · 2021: 20 · 2020: 25 · 2019: 16 · 2018: 8 · 2017: 18 · 2016: 12 · 2015: 10 · 2014: 23 · 2013: 33 · 2012: 25
FWCI
4.00
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Keywords
advanced glycation end products, receptor for advanced glycation end products, hyperglycemia, diabetes complications, cardiovascular disease, inflammation, oxidative stress, 3-deoxyglucosone, polyol pathway, S100/calgranulins, vascular dysfunction, cardiac dysfunction, aging, glycation
MeSH terms
Receptor for Advanced Glycation End Products, Aldehyde Reductase, Animals, Arteriosclerosis, Cardiovascular Diseases, Diabetes Mellitus, Humans, Inflammation, S100 Proteins, Receptors, Immunologic, Signal Transduction, Glycation End Products, Advanced, Tunica Intima, Carotid Artery Injuries, Diabetes Complications

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