Anna M D Watson1, Jiaze Li2, Dian Samijono2, Angelika Bierhaus3, Merlin C Thomas4, Karin A M Jandeleit-Dahm5, Mark E Cooper4. 1. Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia. Electronic address: Anna.Watson@bakeridi.edu.au. 2. Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia. 3. Department of Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany. 4. Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia; Department of Medicine, Central Clinical School, Monash University, Australia. 5. Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia; Department of Medicine, Central Clinical School, Monash University, Australia. Electronic address: karin.jandeleit-dahm@baker.edu.au.
Abstract
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..
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 diabeticapoE 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..
Authors: Stephen P Gray; Jay C Jha; Kit Kennedy; Erik van Bommel; Phyllis Chew; Cedric Szyndralewiez; Rhian M Touyz; Harald H H W Schmidt; Mark E Cooper; Karin A M Jandeleit-Dahm Journal: Diabetologia Date: 2017-02-03 Impact factor: 10.122