CircRNA Chordc1 protects mice from abdominal aortic aneurysm by contributing to the phenotype and growth of vascular smooth muscle cells

• Published in: Molecular therapy. Nucleic acids Vol. 27; pp. 81 - 98
• Main Authors: He, Xiang, Li, Xinzhong, Han, Yuan, Chen, Guojun, Xu, Tong, Cai, Donghua, Sun, Yili, Wang, Shifei, Lai, Yanxian, Teng, Zhonghua, Huang, Senlin, Liao, Wangjun, Liao, Yulin, Bin, Jianping, Xiu, Jiancheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: abdominal aortic aneurysm; ANXA2; apoptosis; CircRNA; Original; phenotypic switching; vimentin; VSMCs; VSMCs; ANXA2; phenotypic switching; apoptosis; vimentin; CircRNA; abdominal aortic aneurysm
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2021.11.005

Circular RNAs (circRNAs) have important potential in modulating vascular smooth muscle cell (VSMC) activity, but their roles in abdominal aortic aneurysm (AAA) are unknown. We performed in situ hybridization and immunohistochemistry and determined that circChordc1 (cysteine and histidine-rich domain containing 1) was markedly downregulated in aneurysm tissue compared with normal arteries. A gene gain and loss strategy was used to confirm that circChordc1 transformed VSMCs into a contracted phenotype and improved their growth, which significantly suppressed aneurysm formation and reduced the risk of rupture in mouse models of angiotensin (Ang) II- and CaCl2-induced AAA. RNA pull-down, immunoprecipitation, and immunoblotting indicated that circChordc1 facilitated the VSMC phenotype and growth determination by binding to vimentin and ANXA2 (annexin A2), which not only increased vimentin phosphorylation to promote its degradation but also promoted the interaction between ANXA2 and glycogen synthase kinase 3 beta (GSK3β) to induce the nuclear entry of β-catenin. Thus, our present study revealed that circChordc1 optimized the VSMC phenotype and improved their growth by inducing vimentin degradation and increasing the activity of the GSK3β/β-catenin pathway, thereby extenuating vascular wall remodeling and reversing pathological aneurysm progression. [Display omitted] Our study identified a VSMC-specific circChordc1, which optimized the VSMC phenotype and improved their growth by inducing vimentin degradation and activating the GSK3β/β-catenin pathway, thereby extenuating vascular wall remodeling, could be an ideal target for preventing abdominal aortic aneurysm formation and progression.