The AGE/RAGE axis in diabetes-accelerated atherosclerosis

Karin Jandeleit-Dahm, Anna Watson, Aino Soro-Paavonen

Research output: Contribution to journalReview ArticleResearchpeer-review

46 Citations (Scopus)

Abstract

1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE-/- mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.

Original languageEnglish
Pages (from-to)329-334
Number of pages6
JournalClinical and Experimental Pharmacology and Physiology
Volume35
Issue number3
DOIs
Publication statusPublished - 1 Mar 2008
Externally publishedYes

Keywords

  • Advanced glycation end-products
  • Apolipoprotein E-knockout mice
  • Atherosclerosis
  • Diabetes
  • Nuclear factor-κB
  • Receptor for advanced glycation end-products (RAGE)
  • Tie2 RAGE transgenic mice

Cite this

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The AGE/RAGE axis in diabetes-accelerated atherosclerosis. / Jandeleit-Dahm, Karin; Watson, Anna; Soro-Paavonen, Aino.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 35, No. 3, 01.03.2008, p. 329-334.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

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AU - Jandeleit-Dahm, Karin

AU - Watson, Anna

AU - Soro-Paavonen, Aino

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N2 - 1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE-/- mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.

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KW - Advanced glycation end-products

KW - Apolipoprotein E-knockout mice

KW - Atherosclerosis

KW - Diabetes

KW - Nuclear factor-κB

KW - Receptor for advanced glycation end-products (RAGE)

KW - Tie2 RAGE transgenic mice

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U2 - 10.1111/j.1440-1681.2007.04875.x

DO - 10.1111/j.1440-1681.2007.04875.x

M3 - Review Article

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AN - SCOPUS:39149106335

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EP - 334

JO - Clinical and Experimental Pharmacology and Physiology

JF - Clinical and Experimental Pharmacology and Physiology

SN - 0305-1870

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