Ages Activate The Local Renin-angiotensin System And Induce Vascular Injury In Small Coronary Arteries Of Stz-induced Diabetic Rats

Background: The concentration of advanced glycation end products (AGEs) parallel the severity of diabetic vasculopathy. Though angiotensinⅡ(ANGⅡ) has a critical role in the progression of diabetic cardiovascular disease, no link has been established between coronary arterial injuries induced by AGEs with the level of activity of the local renin-angiotensin system (RAS) in small coronary arteries. We hypothesized that AGEs/receptor for AGEs (RAGE) contributes to endothelial dysfunction and alterations of structure and function in the small coronary arteries. Furthermore, local RAS in the coronary artery may be activated by the increase of AGEs/RAGE, which would enhance ANGⅡ/ ANGⅡtype 1 receptor (AT1) activities that are associated with coronary arterial vasculopathy in diabetes mellitus (DM).Methods: To test the hypothesis, AGE/ANGⅡlevels and mRNA/protein expression of RAGE/AT1 in small coronary arteries of streptozotocin-induced DM rats, DM rats treated with aminoguanidine, DM rats treated with valsartan and individual control rats were measured by immunohistochemical localization, ELISA assay, Western blot analysis and real-time PCR analysis. The vasomotorial function was evaluated and expression of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), and nuclear factor-кB (NF-кB) p65 were measured. The ultrastructural changes were observed by transmission electron microscope.Results: The data demonstrates that ANGⅡ/AT1 levels were enhanced with the increase of AGEs/RAGE (p<0.05). The KCl/noradrenaline-induced vasoconstrictive function and acetylcholine-induced vasodilative function were decreased in the isolated arteries from DM rats (p<0.05). The vasculopathy was induced through activating NF-κB. The decrease of eNOS and the increase of ET-1 participated in alterations of the vasomotorial function. Local activated RAS resulted in pathological ultrastructural changes of the vascular endothelium. With the reduction of AGEs/RAGE by treatment with aminoguanidine, the level of ANGⅡ/AT1 was decreased and the vasculopathy was lessened. Treatment with valsartan improved the structure and function of the coronary arteries.Conclusions: Our study provides evidence AGEs may activate local RAS in the coronary arteries and induce vascular injury. AT1 receptor antagonist and the blockade of AGEs formation may be effective for the treatment of diabetic coronary vascular disease.