2. Academic Validation
  3. Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation

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

  • J Clin Invest. 2021 Dec 15;131(24):e147031. doi: 10.1172/JCI147031.
Xue Gong 1 2,  Miao Tian 1 2,  Nian Cao 1 2,  Peili Yang 1 3 4,  Zaicheng Xu 1 2,  Shuo Zheng 1 2,  Qiao Liao 1 2,  Caiyu Chen 1 2,  Cindy Zeng 2,  Pedro A Jose 5,  Da-Zhi Wang 6,  Zhao Jian 7,  Yingbin Xiao 7,  Ding-Sheng Jiang 8,  Xiang Wei 8,  Bing Zhang 9,  Yibin Wang 10,  Ken Chen 1 2 11,  Gengze Wu 1 2,  Chunyu Zeng 1 2 11
Affiliations

Affiliations

  • 1 Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
  • 3 College of Medicine, Southwest Jiaotong University, Chengdu, China.
  • 4 Department of Cardiovascular Medicine, The General Hospital of Western Theater Command PLA, Chengdu, China.
  • 5 Division of Renal Disease & Hypertension, Departments of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
  • 6 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 7 Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 8 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
  • 10 Division of Molecular Medicine, Departments of Anesthesiology, Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
  • 11 Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, China.
PMID: 34907911 DOI: 10.1172/JCI147031
Abstract

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.

Keywords

Atherosclerosis; Cardiology; Cardiovascular disease; Epigenetics; Vascular Biology.

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