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Updated: Aug 16, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes
Thoralf Wendt1, Evis Harja, Loredana Bucciarelli
1Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W, 168th Street, Black Building 1705, New York, NY 10032, USA.
Abstract:
Previous studies demonstrated that induction of diabetes with streptozotocin (stz) accelerated atherosclerosis in hyperlipidemic apo E null (-/-) mice. Blockade of the Receptor for Advanced Glycation Endproducts (RAGE) in those animals suppressed acceleration of atherosclerotic lesion area, in a manner independent of changes in levels of glucose, insulin or lipids. In the present studies, we extended these concepts to a murine model of type 2 diabetes, and bred apo E -/- mice into the db/db background. Db/db mice are a model of obesity and insulin resistance-mediated hyperglycemia. Compared to apo E -/- m/db (non-diabetic) mice, apo E -/- db/db (diabetic) mice displayed accelerated atherosclerosis at the aortic sinus. Consistent with an important role for RAGE in this process, administration of soluble (s) RAGE, the extracellular ligand-binding domain of RAGE, resulted in significantly reduced atherosclerotic lesion area in a glycemia- and lipid-independent manner. In parallel, apo E -/- db/db mice displayed RAGE-dependent enhanced expression of Vascular Cell Adhesion Molecule-1, tissue factor and matrix metalloproteinase (MMP)-9 antigen/activity in aortae compared to non-diabetic animals. In addition, consistent with the premise that upregulation of RAGE ligands and RAGE occurs even in the non-diabetic, hyperlipidemic state, albeit to lesser degrees than in diabetes, administration of sRAGE to apo E -/- m/db mice resulted in decreased atherosclerotic lesion area at the aortic sinus. Taken together, these findings establish a new murine model for the study of atherosclerosis in type 2 diabetes and highlight important roles for RAGE in proatherogenic mechanisms in hyperglycemia triggered by insulin resistance.
Insights
This study introduces a new mouse model for type 2 diabetes and atherosclerosis. Blocking the Receptor for Advanced Glycation Endproducts (RAGE) reduced lesion size, independent of glucose or lipids, highlighting RAGE
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Immunology
Background:
- Atherosclerosis is accelerated in diabetic conditions.
- The Receptor for Advanced Glycation Endproducts (RAGE) plays a role in atherosclerosis.
- ApoE null mice are a model for hyperlipidemia-induced atherosclerosis.
Purpose of the Study:
- To establish a new murine model for studying atherosclerosis in type 2 diabetes.
- To investigate the role of RAGE in accelerated atherosclerosis in diabetic mice.
- To determine if RAGE blockade affects atherosclerosis independently of metabolic changes.
Main Methods:
- Bred ApoE null mice onto a db/db background to create a type 2 diabetes model.
- Administered soluble RAGE (sRAGE) to diabetic and non-diabetic hyperlipidemic mice.
- Assessed atherosclerotic lesion area and expression of inflammatory markers (VCAM-1, TF, MMP-9).
Main Results:
- Diabetic ApoE null db/db mice showed accelerated atherosclerosis compared to non-diabetic controls.
- sRAGE administration significantly reduced atherosclerotic lesion area in diabetic mice, independent of glycemia and lipids.
- RAGE blockade also reduced lesion area in non-diabetic hyperlipidemic mice.
- Diabetic mice exhibited increased RAGE-dependent expression of VCAM-1, tissue factor, and MMP-9.
Conclusions:
- ApoE null db/db mice provide a valuable model for type 2 diabetes-associated atherosclerosis.
- RAGE blockade is a potential therapeutic strategy for atherosclerosis in diabetes, acting independently of metabolic control.
- RAGE and its ligands contribute to proatherogenic mechanisms in insulin resistance-mediated hyperglycemia.
