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

作者全名："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."

作者地址："[Li, Yankui; Zheng, Xiaoya; Guo, Jia; Samura, Makoto; Zhao, Sihai; Li, Gang; Shoji, Takahiro; Ikezoe, Toru; Xu, Baohui; Dalman, Ronald L. L.] Stanford Univ, Sch Med, Dept Surg, Room P323,1201 Welch Rd, Stanford, CA 94305 USA; [Li, Yankui] Tianjin Med Univ Second Hosp, Dept Vasc Surg, Tianjin, Peoples R China; [Zheng, Xiaoya] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrinol, Chongqing, Peoples R China; [Ge, Yingbin] Nanjing Med Univ, Dept Physiol, Nanjing, Peoples R China; [Chen, Xiaofeng] Indiana Univ Sch Med, Dept Radiat Oncol, Indianapolis, IN USA; [Miyata, Masaaki] Kagoshima Univ, Fac Med, Sch Hlth Sci, Kagoshima, Japan"

通信作者："Xu, BH; Dalman, RL (通讯作者)，Stanford Univ, Sch Med, Dept Surg, Room P323,1201 Welch Rd, Stanford, CA 94305 USA."

来源：JOURNAL OF THE AMERICAN HEART ASSOCIATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001003633600027

JCR分区：Q1

影响因子：5

年份：2023

卷号：12

期号：10

开始页：　

结束页：　

文献类型：Article

关键词：abdominal aortic aneurysm; advanced glycation end-products (AGEs); cross-linking; diabetes

摘要："BackgroundAlthough 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. Methods and ResultsMale 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. ConclusionsInhibiting 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."

基金机构："National Heart, Lung, and Blood Institute [1R21HL109750, 1R21HL112122]; Walter C. and Elsa R. Chidester Professorship; Department of Surgery at Stanford University; China Scholarship Council; Shanxi Medical University First Hospital Postdoctoral Research Fellowship; National Specialized Clinical Center Program for Endocrinology at Chongqing Medical University; Kyorin University Research Fellowship; Fukuda Foundation for Medical Technology; Uehara Memorial Foundation"

基金资助正文："This work was supported in part by the National Heart, Lung, and Blood Institute (1R21HL109750 and 1R21HL112122) and the Walter C. and Elsa R. Chidester Professorship and the Department of Surgery at Stanford University. Other support was provided by the China Scholarship Council (Gang Li, Yankui Li and Sihai Zhao), Shanxi Medical University First Hospital Postdoctoral Research Fellowship (Jia Guo), National Specialized Clinical Center Program for Endocrinology at Chongqing Medical University (Xiaoya Zheng), Kyorin University Research Fellowship (Toru Ikezoe), Fukuda Foundation for Medical Technology (Takahiro Shoji), and the Uehara Memorial Foundation (Makoto Samura)"