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Published on: September 26, 2018
Quinapril treatment abolishes diabetes-associated atherosclerosis in RAGE/apolipoprotein E double knockout mice
Anna M D Watson1, Jiaze Li1, Dian Samijono1
1Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia.
Objective/Rationale:
Both the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE) potentiate diabetes-associated atherosclerosis (DAA). We assessed the effectiveness of concomitant RAS and RAGE inhibition on DAA.
Methods:
Diabetic (5 × 55 mg/kg streptozotocin daily) and non-diabetic male RAGE/apolipoprotein E double knockout (RAGE/apoE DKO) mice were treated with quinapril (30 mg/kg/day) for 20 weeks. At the end of the study aortic plaques were assessed.
Results:
Diabetic RAGE/apoE DKO showed significantly less plaque area than diabetic apoE KO mice. Plaque deposition was almost abolished in quinapril treated diabetic RAGE/apoE DKOs, with significant attenuation of vascular collagen deposition, nitrotyrosine staining, and reduced macrophage infiltration. Expression of the advanced glycation end product receptor 3 (galectin 3) was also significantly reduced.
Conclusion:
Concomitant inhibition of RAS and RAGE signalling almost completely inhibited the development of experimental DAA. A dual therapeutic approach may be a superior strategy for the treatment of diabetic macrovascular disease..
Insights
Dual inhibition of the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE) significantly reduced diabetes-associated atherosclerosis (DAA) in mice. This combined approach may offer a superior strategy for treating diabetic macrovascular disease.
Area of Science:
- Cardiovascular Research
- Diabetology
- Pharmacology
Background:
- Diabetes-associated atherosclerosis (DAA) is exacerbated by both the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE).
- Understanding the interplay between RAS and RAGE is crucial for developing effective treatments for DAA.
Purpose of the Study:
- To evaluate the efficacy of simultaneously inhibiting RAS and RAGE in mitigating DAA.
- To investigate the therapeutic potential of a dual-targeting strategy for diabetic macrovascular complications.
Main Methods:
- Diabetic and non-diabetic RAGE/apolipoprotein E double knockout (RAGE/apoE DKO) mice were treated with quinapril, an RAS inhibitor.
- Aortic plaque burden and associated markers of inflammation and fibrosis were assessed after 20 weeks of treatment.
Main Results:
- Diabetic RAGE/apoE DKO mice treated with quinapril exhibited nearly complete inhibition of aortic plaque formation.
- Significant reductions in vascular collagen deposition, nitrotyrosine staining, and macrophage infiltration were observed.
- Expression of galectin 3, a marker for RAGE activity, was also significantly decreased.
Conclusions:
- Concomitant inhibition of RAS and RAGE signaling effectively prevents experimental DAA.
- A dual therapeutic approach targeting both pathways presents a promising strategy for managing diabetic macrovascular disease.
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