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RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice
Loredana G Bucciarelli1, Thoralf Wendt, Wu Qu
1Division of Surgical Science, College of Physicians & Surgeons, Department of Surgery, Columbia University, New York, NY 10032, USA.
Background:
Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice.
Methods And Results:
Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed.
Conclusions:
RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.
Insights
Blockading the Receptor for Advanced Glycation End products (RAGE) significantly reduced atherosclerosis progression in established diabetic mouse models. This suggests RAGE blockade could be a new strategy for treating advanced vascular disease in diabetes.
Area of Science:
- Cardiovascular Research
- Diabetes Complications
- Vascular Biology
Background:
- Previous research indicated that blocking Receptor for Advanced Glycation End products (RAGE) could hinder early atherosclerosis in diabetic mice.
- Assessing RAGE blockade's impact on established vascular disease is crucial for clinical applications.
Purpose of the Study:
- To investigate the role of RAGE in the progression of atherosclerosis in established diabetic apolipoprotein E-null mice.
- To test the hypothesis that RAGE blockade can impact established atherosclerotic lesions.
Main Methods:
- Diabetic and control apoE-null mice were treated with soluble RAGE (sRAGE) or albumin from 14 to 20 weeks of age.
- Atherosclerotic lesion area and complexity were analyzed.
- Parameters of inflammation and cell activation were assessed.
Main Results:
- Albumin-treated diabetic mice showed increased atherosclerotic lesion area and complexity.
- sRAGE treatment significantly reduced lesion area and complexity in diabetic mice.
- sRAGE treatment also decreased inflammation and cell activation markers.
Conclusions:
- Receptor for Advanced Glycation End products (RAGE) plays a role in both the formation and progression of atherosclerotic lesions in diabetic mice.
- RAGE blockade presents a potential therapeutic strategy for stabilizing established atherosclerosis and associated vascular inflammation in diabetic patients.
