Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
Department of Chemistry, Kurume University School of Medicine, Kurume, Japan.
Int J Cardiol. 2014 Feb 15;171(3):443-6. doi: 10.1016/j.ijcard.2013.12.143. Epub 2014 Jan 8.
Advanced glycation end products (AGE) and their receptor (RAGE) interaction elicit inflammatory and proliferative reactions in arteries, thus playing a role in cardiovascular disease. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. However, effects of AGE-aptamer on vascular injury remain unknown. In this study, we examined whether and how AGE-aptamer inhibits neointimal hyperplasia in balloon-injured rat carotid arteries.
Male Wistar rats (weighting ca. 400 g at 11 weeks old) were anesthetized with sodium pentobarbital. The left common carotid artery was balloon-injured 3 times with 2F Fogaty catheter inserted through the femoral artery. Then the rats received continuous intraperitoneal infusion (3 μg/day) of either AGE-aptamer or control-aptamer by an osmotic mini pump for 2 weeks. 14 days after the procedure, the left common carotid arteries were excised for morphometric, immunohistochemical and western blot analyses.
Compared with control-aptamer, AGE-aptamer significantly suppressed neointima formation after balloon injury and reduced AGE accumulation, oxidative stress generation, proliferation cell nuclear antigen-positive area, macrophage infiltration, RAGE and platelet-derived growth factor-BB (PDGF-BB) expression levels in balloon-injured carotid arteries.
The present study suggests that AGE-aptamer could prevent balloon injury-induced neointimal hyperplasia by reducing PDGF-BB and macrophage infiltration via suppression of the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for suppressing neointima formation after balloon angioplasty.
晚期糖基化终产物（AGE）及其受体（RAGE）相互作用会在动脉中引发炎症和增殖反应，从而在心血管疾病中发挥作用。我们最近发现，针对 AGE 的高亲和力 DNA 适体（AGE-适体）通过阻断 AGE 在肾脏中的有害作用，可防止实验性糖尿病肾病的进展。然而，AGE-适体对血管损伤的影响尚不清楚。在这项研究中，我们研究了 AGE-适体是否以及如何抑制球囊损伤大鼠颈总动脉的内膜增生。
雄性 Wistar 大鼠（11 周龄时体重约 400g）用戊巴比妥钠麻醉。通过股动脉插入 2F Fogaty 导管 3 次对左颈总动脉进行球囊损伤。然后，通过渗透型迷你泵以每天 3μg 的剂量连续向大鼠腹膜内输注 AGE-适体或对照适体 2 周。在手术后 14 天，取出左颈总动脉进行形态计量学、免疫组织化学和 Western blot 分析。
与对照适体相比，AGE-适体可显著抑制球囊损伤后的新生内膜形成，并减少 AGE 积累、氧化应激产生、增殖细胞核抗原阳性面积、巨噬细胞浸润、RAGE 和血小板衍生生长因子-BB（PDGF-BB）在球囊损伤颈动脉中的表达水平。
本研究表明，AGE-适体通过抑制 AGE-RAGE 介导的氧化应激产生，减少 PDGF-BB 和巨噬细胞浸润，可预防球囊损伤引起的内膜增生。AGE-适体可能是抑制球囊血管成形术后内膜形成的一种新的治疗策略。
