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


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-kappaB 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.
Soro-Paavonen
Aino
A
Albert Einstein Juvenile Diabetes Research Foundation Centre for Diabetes Complications, Diabetes Metabolism Division, Baker Heart Research Institute, Melbourne, Australia.
Watson
Anna M D
AM
Li
Jiaze
J
Paavonen
Karri
K
Koitka
Audrey
A
Calkin
Anna C
AC
Barit
David
D
Coughlan
Melinda T
MT
Drew
Brian G
BG
Lancaster
Graeme I
GI
Thomas
Merlin
M
Forbes
Josephine M
JM
Nawroth
Peter P
PP
Bierhaus
Angelika
A
Cooper
Mark E
ME
Jandeleit-Dahm
Karin A
KA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers; D003094:Collagen / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D004734:Energy Metabolism / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D014657:Vasculitis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
D001057:Apolipoproteins E; D015415:Biomarkers; D017127:Glycation End Products, Advanced; D044140:Receptor, Angiotensin, Type 1; D003094:Collagen; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases