Watson Anna M D, Li Jiaze, Samijono Dian, Bierhaus Angelika, Thomas Merlin C, Jandeleit-Dahm Karin A M, Cooper Mark E
Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia.
Diabetes Complications-Diabetes and The Kidney Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia.
Atherosclerosis. 2014 Aug;235(2):444-8. doi: 10.1016/j.atherosclerosis.2014.05.945. Epub 2014 Jun 4.
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.
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.
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.
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..
目的/基本原理：肾素-血管紧张素系统（RAS）和晚期糖基化终产物受体（RAGE）均会加重糖尿病相关动脉粥样硬化（DAA）。我们评估了同时抑制RAS和RAGE对DAA的疗效。
将糖尿病（每日5×55mg/kg链脲佐菌素）和非糖尿病雄性RAGE/载脂蛋白E双敲除（RAGE/apoE DKO）小鼠用喹那普利（30mg/kg/天）治疗20周。在研究结束时评估主动脉斑块情况。
糖尿病RAGE/apoE DKO小鼠的斑块面积显著小于糖尿病apoE KO小鼠。在喹那普利治疗的糖尿病RAGE/apoE DKO小鼠中，斑块沉积几乎消失，血管胶原沉积、硝基酪氨酸染色显著减轻，巨噬细胞浸润减少。晚期糖基化终产物受体3（半乳糖凝集素3）的表达也显著降低。
同时抑制RAS和RAGE信号传导几乎完全抑制了实验性DAA的发展。双重治疗方法可能是治疗糖尿病大血管疾病的更优策略。
