Treatment With Small Molecule Inhibitors of Advanced Glycation End-Products Formation and Advanced Glycation End-Products-Mediated Collagen Cross-Linking Promotes Experimental Aortic Aneurysm Progression in Diabetic Mice.
Treatment With Small Molecule Inhibitors of Advanced Glycation End-Products Formation and Advanced Glycation End-Products-Mediated Collagen Cross-Linking Promotes Experimental Aortic Aneurysm Progression in Diabetic Mice.
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DOI：
10.1161/jaha.122.028081
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发表时间：
2023-05-16
影响因子：
5.4
通讯作者：
Dalman, Ronald L. L.
中科院分区：
文献类型：
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作者：
Li, Yankui;Zheng, Xiaoya;Guo, Jia;Samura, Makoto;Ge, Yingbin;Zhao, Sihai;Li, Gang;Chen, Xiaofeng;Shoji, Takahiro;Ikezoe, Toru;Miyata, Masaaki;Xu, Baohui;Dalman, Ronald L. L.
虽然糖尿病能减轻腹主动脉瘤（AAAs），但糖尿病抑制腹主动脉瘤的机制仍不完全清楚。晚期糖基化末端（AGEs）的积累可减少糖尿病患者细胞外基质（ECM）的降解。由于ECM降解对AAA发病机制至关重要，我们研究了AGEs是否通过阻断AGE形成或使用小分子抑制剂破坏AGE - ECM交联来介导实验性糖尿病AAA抑制。用链脲佐菌素和主动脉内弹性蛋白酶分别诱导雄性C57BL/6J小鼠糖尿病和实验性AAAs。从注射链脲佐菌素后的最后一天开始，每天给小鼠氨基胍（AGE形成抑制剂，200 mg/kg）、白藜芦醇（AGE‐ECM交联干扰物，20 mg/kg）或对照物。通过连续主动脉直径测量、组织病理学和体外内侧弹性溶解试验来评估AAAs。氨基胍治疗，而不是镓治疗，降低了糖尿病AAAs的AGEs。与载药治疗相比，两种抑制剂治疗均能增强糖尿病小鼠的主动脉扩张。两者均不能增强非糖尿病小鼠的AAA增大。氨基胍或alagbrium治疗增强糖尿病小鼠的AAA，促进弹性蛋白降解、平滑肌细胞耗竭、壁巨噬细胞积累和新生血管生成，而不影响基质金属蛋白酶、C‐C基序趋化因子配体2或血清葡萄糖浓度。此外，在体外实验中，用这两种抑制剂治疗可以逆转猪胰腺弹性酶对糖尿病主动脉内侧弹性溶解的抑制。抑制AGE形成或AGE - ECM交联可增强实验性糖尿病中的AAAs。这些发现支持了AGEs减弱实验性糖尿病AAAs的假设。这些发现强调了增强ECM交联作为早期AAA疾病抑制策略的潜在转化价值。
Although diabetes attenuates abdominal aortic aneurysms (AAAs), the mechanisms by which diabetes suppresses AAAs remain incompletely understood. Accumulation of advanced glycation end‐ (AGEs) reduces extracellular matrix (ECM) degradation in diabetes. Because ECM degradation is critical for AAA pathogenesis, we investigated whether AGEs mediate experimental AAA suppression in diabetes by blocking AGE formation or disrupting AGE‐ECM cross‐linking using small molecule inhibitors. Male C57BL/6J mice were treated with streptozotocin and intra‐aortic elastase infusion to induce diabetes and experimental AAAs, respectively. Aminoguanidine (AGE formation inhibitor, 200 mg/kg), alagebrium (AGE‐ECM cross‐linking disrupter, 20 mg/kg), or vehicle was administered daily to mice from the last day following streptozotocin injection. AAAs were assessed via serial aortic diameter measurements, histopathology, and in vitro medial elastolysis assays. Treatment with aminoguanidine, not alagebrium, diminished AGEs in diabetic AAAs. Treatment with both inhibitors enhanced aortic enlargement in diabetic mice as compared with vehicle treatment. Neither enhanced AAA enlargement in nondiabetic mice. AAA enhancement in diabetic mice by aminoguanidine or alagebrium treatment promoted elastin degradation, smooth muscle cell depletion, mural macrophage accumulation, and neoangiogenesis without affecting matrix metalloproteinases, C‐C motif chemokine ligand 2, or serum glucose concentration. Additionally, treatment with both inhibitors reversed suppression of diabetic aortic medial elastolysis by porcine pancreatic elastase in vitro. Inhibiting AGE formation or AGE‐ECM cross‐linking enhances experimental AAAs in diabetes. These findings support the hypothesis that AGEs attenuate experimental AAAs in diabetes. These findings underscore the potential translational value of enhanced ECM cross‐linking as an inhibitory strategy for early AAA disease.
影响因子：
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作者：
Zhang, Simeng;Liu, Jie;Jia, Xin;Zhang, Tao;Qin, Xianhui;Jia, Senhao;Li, Yue;Liu, Lishun;Song, Yuxiang;Zuo, Shangwei;Wei, Ren;Duan, Chen;Wu, Zhongyin;Ge, Yangyang;Wang, Xian;Kong, Wei;Xu, Xiping;Wang, Qiang;Huo, Yong;Guo, Wei
通讯作者：
Guo, Wei
DOI：
10.1016/j.jss.2010.04.027
发表时间：
2011-12
期刊：
The Journal of surgical research
影响因子：
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作者：
Zhang F;Banker G;Liu X;Suwanabol PA;Lengfeld J;Yamanouchi D;Kent KC;Liu B
通讯作者：
Liu B