RAGE mediates accelerated diabetic vein graft atherosclerosis induced by combined mechanical stress and AGEs via synergistic ERK activation.
RAGE mediates accelerated diabetic vein graft atherosclerosis induced by combined mechanical stress and AGEs via synergistic ERK activation.
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RAGE 通过协同 ERK 激活介导机械应力和 AGE 联合诱导的加速糖尿病静脉移植物动脉粥样硬化
DOI：
10.1371/journal.pone.0035016
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Li Y;Liu S;Zhang Z;Xu Q;Xie F;Wang J;Ping S;Li C;Wang Z;Zhang M;Huang J;Chen D;Hu L;Li C
目的/假设糖尿病合并高血压可迅速加速血管疾病，但其潜在机制尚不清楚。我们评估了晚期糖基化终产物受体(RAGE)可能介导糖尿病相关AGEs和高血压诱导的机械应激启动的联合信号的假设，作为一种常见的分子传感器。方法将C57BL/6J小鼠的下腔静脉段移植到链脲佐菌素(STZ)处理和未处理的同基因小鼠的颈总动脉内，用形态计量学和免疫组织化学方法对移植静脉进行了分析。体外培养RAGE基因表达下调或过表达的静止小鼠血管平滑肌细胞(VSMCs)，分别在AGEs和AGEs作用下进行循环拉伸。观察细胞外信号调节激酶(ERK)的磷酸化和Ki-67的表达。结果STZ诱导的糖尿病小鼠移植静脉新生内膜形成、AGE沉积、Ki-67表达和RAGE显著增加。在拉伸应激和AGE联合作用下，VSMC中ERK磷酸化和Ki-67表达水平最高。SiRNA-RAGE可显著抑制ERKs和Ki-67在VSMCs中的协同激活，而过度表达RAGE则可增强ERKs和Ki-67的协同激活。结论RAGE可能在机械牵张加AGEs和不加AGEs时协同促进ERK激活和VSMC增殖。它可能是两者之间共同的分子桥梁，加速血管重塑。本研究为糖尿病合并高血压所致血管疾病的治疗提供了潜在的药物靶点和新的治疗策略。
Aims/Hypothesis Diabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor. Methods In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signal-regulated kinase (ERK) phosphorylation and Ki-67 expression were investigated. Results Significant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE. Conclusion RAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanical stretching with and without AGEs. It may serve as a common molecular bridge between the two, accelerating vascular remodeling. This study provides potential drug targets and novel therapeutic strategies for the treatment of vascular diseases resulting from diabetes with hypertension.
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影响因子：
37.8
作者：
Koka, V;Wang, WS;Lan, HY
通讯作者：
Lan, HY
DOI：
10.1152/ajpheart.01047.2006
发表时间：
2007-03-01
影响因子：
4.8
作者：
Chien, Shu
通讯作者：
Chien, Shu
DOI：
10.1007/s11596-007-0411-8
发表时间：
2007-08-01
影响因子：
--
作者：
Cheng Zhengjiang;Hu Lihua;Liao Xiaofeng
通讯作者：
Liao Xiaofeng
影响因子：
37.8
作者：
Bucciarelli, LG;Wendt, T;Schmidt, AM
通讯作者：
Schmidt, AM
影响因子：
8.3
作者：
DOBRIN, PB
通讯作者：
DOBRIN, PB