Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes

Aino Soro-Paavonen, Anna M.D. Watson, Jiaze Li, Karri Paavonen, Audrey Koitka, Anna C. Calkin, David Barit, Melinda T. Coughlan, Brian G. Drew, Graeme I. Lancaster, Merlin Thomas, Josephine M. Forbes, Peter P. Nawroth, Angelika Bierhaus, Mark E. Cooper, Karin A. Jandeleit-Dahm

Research output: Contribution to journalArticleResearchpeer-review

Abstract

OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE-/- model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoE-/- and RAGE-/-/ apoE-/- double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoE-/- mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE-/-/apoE-/- mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE-/- mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE-/- mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE -/-/apoE-/- mice. CONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.

Original languageEnglish
Pages (from-to)2461-2469
Number of pages9
JournalDiabetes
Volume57
Issue number9
DOIs
Publication statusPublished - 1 Sep 2008
Externally publishedYes

Cite this

@article{d80263b8b8e5412cb6a3c003165f3bcd,
title = "Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes",
abstract = "OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE-/- model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoE-/- and RAGE-/-/ apoE-/- double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoE-/- mice showed increased plaque accumulation (14.9 ± 1.7{\%}), diabetic RAGE-/-/apoE-/- mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4{\%}) to levels not significantly different from control apoE-/- mice (4.3 ± 0.4{\%}). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE-/- mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE -/-/apoE-/- mice. CONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.",
author = "Aino Soro-Paavonen and Watson, {Anna M.D.} and Jiaze Li and Karri Paavonen and Audrey Koitka and Calkin, {Anna C.} and David Barit and Coughlan, {Melinda T.} and Drew, {Brian G.} and Lancaster, {Graeme I.} and Merlin Thomas and Forbes, {Josephine M.} and Nawroth, {Peter P.} and Angelika Bierhaus and Cooper, {Mark E.} and Jandeleit-Dahm, {Karin A.}",
year = "2008",
month = "9",
day = "1",
doi = "10.2337/db07-1808",
language = "English",
volume = "57",
pages = "2461--2469",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "9",

}

Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. / Soro-Paavonen, Aino; Watson, Anna M.D.; Li, Jiaze; Paavonen, Karri; Koitka, Audrey; Calkin, Anna C.; Barit, David; Coughlan, Melinda T.; Drew, Brian G.; Lancaster, Graeme I.; Thomas, Merlin; Forbes, Josephine M.; Nawroth, Peter P.; Bierhaus, Angelika; Cooper, Mark E.; Jandeleit-Dahm, Karin A.

In: Diabetes, Vol. 57, No. 9, 01.09.2008, p. 2461-2469.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes

AU - Soro-Paavonen, Aino

AU - Watson, Anna M.D.

AU - Li, Jiaze

AU - Paavonen, Karri

AU - Koitka, Audrey

AU - Calkin, Anna C.

AU - Barit, David

AU - Coughlan, Melinda T.

AU - Drew, Brian G.

AU - Lancaster, Graeme I.

AU - Thomas, Merlin

AU - Forbes, Josephine M.

AU - Nawroth, Peter P.

AU - Bierhaus, Angelika

AU - Cooper, Mark E.

AU - Jandeleit-Dahm, Karin A.

PY - 2008/9/1

Y1 - 2008/9/1

N2 - OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE-/- model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoE-/- and RAGE-/-/ apoE-/- double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoE-/- mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE-/-/apoE-/- mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE-/- mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE-/- mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE -/-/apoE-/- mice. CONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.

AB - OBJECTIVE-Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE-/- model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS-ApoE-/- and RAGE-/-/ apoE-/- double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS-Although diabetic apoE-/- mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE-/-/apoE-/- mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE-/- mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE-/- mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE -/-/apoE-/- mice. CONCLUSIONS-This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.

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U2 - 10.2337/db07-1808

DO - 10.2337/db07-1808

M3 - Article

VL - 57

SP - 2461

EP - 2469

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -