MicroRNA-199a-5p aggravates angiotensin II-induced vascular smooth muscle cell senescence by targeting Sirtuin-1 in abdominal aortic aneurysm

作者:Tao, Wuyuan; Hong, Yimei; He, Haiwei; Han, Qian; Mao, Mengmeng; Hu, Bei; Zhang, Hao; Huang, Xiaoran; You, Wei; Liang, Xiaoting; Zhang, Yuelin*; Li, Xin*
来源:Journal of Cellular and Molecular Medicine, 2021, 25(13): 6056-6069.
DOI:10.1111/jcmm.16485

摘要

Vascular smooth muscle cells (VSMCs) senescence contributes to abdominal aortic aneurysm (AAA) formation although the underlying mechanisms remain unclear. This study aimed to investigate the role of miR-199a-5p in regulating VSMC senescence in AAA. VSMC senescence was determined by a senescence-associated beta-galactosidase (SA-beta-gal) assay. RT-PCR and Western blotting were performed to measure miRNA and protein level, respectively. The generation of reactive oxygen species (ROS) was evaluated by H2DCFDA staining. Dual-luciferase reporter assay was used to validate the target gene of miR-199a-5p. VSMCs exhibited increased senescence in AAA tissue relative to healthy aortic tissue from control donors. Compared with VSMCs isolated from control donors (control-VSMCs), those derived from patients with AAA (AAA-VSMCs) exhibited increased cellular senescence and ROS production. Angiotensin II (Ang II) induced VSMC senescence by promoting ROS generation. The level of miR-199a-5p expression was upregulated in the plasma from AAA patients and Ang II-treated VSMCs. Mechanistically, Ang II treatment significantly elevated miR-199a-5p level, thereby stimulating ROS generation by repressing Sirt1 and consequent VSMC senescence. Nevertheless, Ang II-induced VSMC senescence was partially attenuated by a miR-199a-5p inhibitor or Sirt1 activator. Our study revealed that miR-199a-5p aggravates Ang II-induced VSMC senescence by targeting Sirt1 and that miR-199a-5p is a potential therapeutic target for AAA.

  • 单位
    广东省人民医院; 1; 同济大学; 广州医学院; 南方医科大学