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：Yankui Li, Xiaoya Zheng, Jia Guo, Makoto Samura, Yingbin Ge, Sihai Zhao, Gang Li, Xiaofeng Chen, Takahiro Shoji, Toru Ikezoe, Masaaki Miyata, Baohui Xu, Ronald L. Dalman · 发表于：Journal of the American Heart Association · 年份：2023 · DOI：10.1161/jaha.122.028081 · 被引用次数：17 · 研究领域：Aortic aneurysm repair treatments、Aortic Disease and Treatment Approaches、Advanced Glycation End Products research

Background 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. Methods and Results 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 gluco...