Chen Yihong, Niu Wenhao, Chao Yu-Chieh, He Zhiqing, Ding Ru, Wu Feng, Liang Chun
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University No. 415, Fengyang Road, Huangpu District, Shanghai 200003, China.
Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University No. 1630, Dongfang Road, Pudong New District, Shanghai 200127, China.
Am J Transl Res. 2019 Mar 15;11(3):1569-1580. eCollection 2019.
N-carboxymethyl-lysine (CML), a major isoform of advanced glycation end products (AGEs), plays a crucial role in the functional damage of diabetes mellitus. However, it is not clear whether ALT-711 (alagebrium), an inhibitor of AGEs, is capable to rescue CML-induced poor angiogenesis, as well as the underlying mechanism. MicroRNA-27b (miR-27b) promotes angiogenesis through down-regulation of anti-angiogenic protein thrombospondin-1 (TSP-1). Here, we used diabetic mice with hindlimb ischemia to investigate whether miR-27b/TSP-1 signaling is involved in the pathology of critical limb ischemia (CLI) in diabetes mellitus. We additionally examined the effect of ALT-711 on the tube formation of endothelial cells treated with CML-BSA. Compared with control group, the lower blood flow recovery was observed in the ischemic lower limbs of diabetic mice, with decreased expression of vascular endothelial growth factor (VEGF) and miR-27b and increased TSP-1 expression. CML-BSA reduced the tube formation ability of endothelial cells, decreased VEGF and miR-27b expression, and increased TSP-1 expression, whereas this trend was reversed by ALT-711. The miR-27b mimic promoted tube formation, increased VEGF expression, and decreased TSP-1 expression, whereas these effects were abolished by TSP-1 overexpression. Moreover, miR-27b silencing suppressed ALT-711-induced promotion of tube formation under CML-BSA treatment, with reduced VEGF and augmented TSP-1 expression. Taken together, the present study demonstrated that ALT-711 can rescue CML-induced functional angiogenesis damage via miR-27b/TSP-1 signaling cascades. These results indicate new therapeutic strategies for diabetes patients with CLI.
N-羧甲基赖氨酸（CML）是晚期糖基化终末产物（AGEs）的主要异构体，在糖尿病的功能损害中起关键作用。然而，AGEs抑制剂ALT-711（阿格列汀）是否能够挽救CML诱导的血管生成不良及其潜在机制尚不清楚。微小RNA-27b（miR-27b）通过下调抗血管生成蛋白血小板反应蛋白-1（TSP-1）促进血管生成。在此，我们使用后肢缺血的糖尿病小鼠来研究miR-27b/TSP-1信号通路是否参与糖尿病下肢严重缺血（CLI）的病理过程。我们还研究了ALT-711对用CML-BSA处理的内皮细胞管形成的影响。与对照组相比，糖尿病小鼠缺血下肢的血流恢复较低，血管内皮生长因子（VEGF）和miR-27b表达降低，TSP-1表达增加。CML-BSA降低了内皮细胞的管形成能力，降低了VEGF和miR-27b表达，并增加了TSP-1表达，而ALT-711逆转了这种趋势。miR-27b模拟物促进管形成，增加VEGF表达，并降低TSP-1表达，而TSP-1过表达消除了这些作用。此外，miR-27b沉默抑制了ALT-711在CML-BSA处理下诱导的管形成促进作用，同时降低了VEGF并增加了TSP-1表达。综上所述，本研究表明ALT-711可通过miR-27b/TSP-1信号级联挽救CML诱导的功能性血管生成损伤。这些结果为糖尿病CLI患者指明了新的治疗策略。
