Hsa_circ_0001402 alleviates vascular neointimal hyperplasia through a miR-183-5p-dependent regulation of vascular smooth muscle cell proliferation, migration, and autophagy

Jia-Jie Lin; Rui Chen; Li-Yun Yang; Miao Gong; Mei-Yang Du; Shi-Qing Mu; Ze-An Jiang; Huan-Huan Li; Yang Yang; Xing-Hui Wang; Si-Fan Wang; Ke-Xin Liu; Shan-Hu Cao; Zhao-Yi Wang; An-Qi Zhao; Shu-Yan Yang; Cheng Li; Shao-Guang Sun

doi:10.1016/j.jare.2023.07.010

Hsa_circ_0001402 alleviates vascular neointimal hyperplasia through a miR-183-5p-dependent regulation of vascular smooth muscle cell proliferation, migration, and autophagy

J Adv Res. 2023 Jul 25:S2090-1232(23)00201-1. doi: 10.1016/j.jare.2023.07.010. Online ahead of print.

Authors

Jia-Jie Lin¹, Rui Chen², Li-Yun Yang¹, Miao Gong¹, Mei-Yang Du¹, Shi-Qing Mu¹, Ze-An Jiang¹, Huan-Huan Li¹, Yang Yang¹, Xing-Hui Wang¹, Si-Fan Wang¹, Ke-Xin Liu¹, Shan-Hu Cao¹, Zhao-Yi Wang¹, An-Qi Zhao¹, Shu-Yan Yang³, Cheng Li⁴, Shao-Guang Sun⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang 050017, China.
² Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
³ Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: shuyanyang79@126.com.
⁴ Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou 510317, China. Electronic address: LiC@gd2h.org.cn.
⁵ Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: sunshaoguang00@163.com.

PMID: 37499939
DOI: 10.1016/j.jare.2023.07.010

Abstract

Introduction: Vascular neointimal hyperplasia, a pathological process observed in cardiovascular diseases such as atherosclerosis and pulmonary hypertension, involves the abundant presence of vascular smooth muscle cells (VSMCs). The proliferation, migration, and autophagy of VSMCs are associated with the development of neointimal lesions. Circular RNAs (circRNAs) play critical roles in regulating VSMC proliferation and migration, thereby participating in neointimal hyperplasia. However, the regulatory roles of circRNAs in VSMC autophagy remain unclear.

Objectives: We aimed to identify circRNAs that are involved in VSMC autophagy-mediated neointimal hyperplasia, as well as elucidate the underlying mechanisms.

Methods: Dual-luciferase reporter gene assay was performed to validate two competing endogenous RNA axes, hsa_circ_0001402/miR-183-5p/FKBP prolyl isomerase like (FKBPL) and hsa_circ_0001402/miR-183-5p/beclin 1 (BECN1). Cell proliferation and migration analyses were employed to investigate the effects of hsa_circ_0001402, miR-183-5p, or FKBPL on VSMC proliferation and migration. Cell autophagy analysis was conducted to reveal the role of hsa_circ_0001402 or miR-183-5p on VSMC autophagy. The role of hsa_circ_0001402 or miR-183-5p on neointimal hyperplasia was evaluated using a mouse model of common carotid artery ligation.

Results: Hsa_circ_0001402 acted as a sponge for miR-183-5p, leading to the suppression of miR-183-5p expression. Through direct interaction with the coding sequence (CDS) of FKBPL, miR-183-5p promoted VSMC proliferation and migration by decreasing FKBPL levels. Besides, miR-183-5p reduced BECN1 levels by targeting the 3'-untranslated region (UTR) of BECN1, thus inhibiting VSMC autophagy. By acting as a miR-183-5p sponge, overexpression of hsa_circ_0001402 increased FKBPL levels to inhibit VSMC proliferation and migration, while simultaneously elevating BECN1 levels to activate VSMC autophagy, thereby alleviating neointimal hyperplasia.

Conclusion: Hsa_circ_0001402, acting as a miR-183-5p sponge, increases FKBPL levels to inhibit VSMC proliferation and migration, while enhancing BECN1 levels to activate VSMC autophagy, thus alleviating neointimal hyperplasia. The hsa_circ_0001402/miR-183-5p/FKBPL axis and hsa_circ_0001402/miR-183-5p/BECN1 axis may offer potential therapeutic targets for neointimal hyperplasia.

Keywords: Autophagy; Migration; Neointima hyperplasia; Proliferation; Vascular smooth muscle cell; hsa_circ_0001402; miR-183-5p.