Journal Article

Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation

Zhang, Bing, Tian, Miao, Cao, Nian, Yang, Peili, Liao, Qiao, Zheng, Shuo, Wang, Da-Zhi, Xiao, Yingbin, Xu, Zaicheng, Jian, Zhao, Wang, Yibin, Zeng, Chunyu, Zeng, Cindy, Wu, Gengze, Chen, Caiyu, Gong, Xue, Chen, Ken, Wei, Xiang, Jose, Pedro A., Jiang, Ding-Sheng

2021

Overview

Circular RNAs (circRNAs) have been recently recognized as playing a role in the pathogenesis of vascular remodeling-related diseases by modulating the functions of miRNAs. However, the interplay between circRNAs and proteins during vascular remodeling remains poorly understood. Here, we investigated a previously identified circRNA, circEsyt2, whose expression is known to be upregulated during vascular remodeling. Loss- and gain-of‑function mutation analyses in vascular smooth muscle cells (VSMCs) revealed that circEsyt2 enhanced cell proliferation and migration and inhibited apoptosis and differentiation. Furthermore, the silencing of circEsyt2 in vivo reduced neointima formation, while circEsyt2 overexpression enhanced neointimal hyperplasia in the injured carotid artery, confirming its role in vascular remodeling. Using unbiased protein-RNA screening and molecular validation, circEsyt2 was found to directly interact with polyC-binding protein 1 (PCBP1), an RNA splicing factor, and regulate PCBP1 intracellular localization. Additionally, circEsyt2 silencing substantially enhanced p53β splicing via the PCBP1-U2AF65 interaction, leading to the altered expression of p53 target genes (cyclin D1, p21, PUMA, and NOXA) and the decreased proliferation of VSMCs. Thus, we identified a potentially novel circRNA that regulated vascular remodeling, via altered RNA splicing, in atherosclerotic mouse models.

• Publisher: American Society for Clinical Investigation
• Subject: Animal models / Animals / Apoptosis / Arteriosclerosis / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - metabolism / Biomedical research / Cardiovascular disease / Care and treatment / Carotid arteries / Carotid artery / Cell migration / Cell Proliferation / Circular RNA / Cyclin D1 / Development and progression / Disease Models, Animal / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Gene expression / Genetic aspects / Genetic screening / Health aspects / Hyperplasia / Hyperplasia - genetics / Hyperplasia - metabolism / Localization / Mice / Mice, Knockout, ApoE / MicroRNA / Muscle, Smooth, Vascular - metabolism / Myocytes, Smooth Muscle - metabolism / p53 Protein / Proteins / Ribonucleic acid / RNA / RNA Splicing / RNA, Circular - genetics / RNA, Circular - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Smooth muscle / Splicing Factor U2AF - genetics / Splicing Factor U2AF - metabolism / Splicing factors / Tumor Suppressor Protein p53 - biosynthesis / Tumor Suppressor Protein p53 - genetics / Vascular Remodeling