Key Takeaways & Executive Findings
- •• lncRNA H19 overexpression promotes VSMC proliferation and migration, exacerbating neointima formation in a mouse carotid ligation model. • Mechanistically, lncRNA H19 acts as a ceRNA for miR-125a-3p, relieving its inhibition on FLT1 expression in VSMCs. • miR-125a-3p upregulation attenuates H19-induced VSMC proliferation and migration, and reduces FLT1 expression, suggesting a potential therapeutic axis. • Targeting lncRNA H19 or miR-125a-3p/FLT1 axis may offer a novel strategy for preventing vascular restenosis after angioplasty or stenting.
Abstract
The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of neointima formation in vascular restenosis. This study aims to explore the function of the long noncoding RNA H19 in neointima formation. A mouse carotid ligation model was established, and human vascular smooth muscle cells (VSMCs) were used as a cell model. lncRNA H19 overexpression promoted VSMC proliferation and migration. Moreover, miR-125a-3p potentially bound to lncRNA H19, and Fms-like tyrosine kinase-1 (FLT1) might be a direct target of miR-125a-3p in VSMCs. Upregulation of miR-125a-3p alleviated lncRNA H19-enhanced VSMC proliferation and migration. Furthermore, rescue experiments showed that enhanced expression of miR-125a-3p attenuated lncRNA H19-induced FLT1 expression in VSMCs. In addition, the overexpression of lncRNA H19 significantly exacerbated neointima formation in a mouse carotid ligation model. In summary, lncRNA H19 stimulates VSMC proliferation and migration by acting as a competing endogenous RNA (ceRNA) of miR-125a-3p. lncRNA H19 may be a therapeutic target for restenosis.
1. Introduction
Cardiovascular disease is the main cause of mortality globally. With the development of endovascular surgery, the prognosis of patients with vascular disease has improved. However, restenosis after angioplasty or stenting remains a major clinical problem [1,2]. The proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to neointima formation, which leads to vascular restenosis [3–5]. Therefore, it is urgent to elucidate the molecular mechanism underlying neointima formation.
Recent studies have reported that long noncoding RNAs (lncRNAs) have various biological functions, such as transcriptional regulation, protein degradation and chromatin stabilization [6,7]. Moreover, lncRNAs are involved in various diseases, such as cancer, neurological disease and heart disease [8–10]. In particular, the lncRNA H19 is located on chromosome 11 and promotes several types of cancer [11,12]. Sun et al. [13] reported that H19 knockdown may prevent atherosclerosis deterioration through increased p53-mediated VSMC apoptosis. In addition, lncRNA H19 promoted the proliferation of VSMCs in a miR-675-dependent manner [14]. Nevertheless, the role of lncRNA H19 in vascular neointima formation has not been well elucidated.
In this study, we found that lncRNA H19 overexpression significantly promoted neointima formation in vivo and VSMC proliferation and migration in vitro. Mechanistically, we found that lncRNA H19 acted as a ceRNA of miR-125a-3p and facilitated the expression of the miR-125a-3p target FLT1 in VSMCs. We further demonstrated that lncRNA H19 knockdown significantly reduced the expression of FLT1. Moreover, overexpression of miR-125a-3p inhibited the proliferation and migration of VSMCs by targeting FLT1.
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Rengui Jiang, Xuyu He, Weidong Chen, Huoying Cai, Zhaohai Su, Zheng Xie, Bilong Zhang, Jiangyong Yang, Yueting Wang, Ling Huang, Gang Cao, Xiutong Zhong, Hui Xie, Hengqing Zhu, Jun Cao, Weiling Lu (2026). lncRNA H19 facilitates vascular neointima formation by targeting miR-125a-3p/FLT1 axis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024087
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Frequently Asked Questions
What is the role of lncRNA H19 in vascular neointima formation?
The study demonstrates that lncRNA H19 overexpression promotes vascular smooth muscle cell (VSMC) proliferation and migration, and exacerbates neointima formation in a mouse carotid ligation model, suggesting it contributes to vascular restenosis.
How does lncRNA H19 regulate VSMC function?
lncRNA H19 acts as a competing endogenous RNA (ceRNA) for miR-125a-3p, thereby relieving miR-125a-3p-mediated inhibition of its target FLT1, leading to increased FLT1 expression and enhanced VSMC proliferation and migration.
What is the significance of the miR-125a-3p/FLT1 axis in this context?
miR-125a-3p directly targets FLT1 and its upregulation attenuates lncRNA H19-induced VSMC proliferation and migration, indicating that the miR-125a-3p/FLT1 axis is a key downstream mediator of lncRNA H19 effects.
Could lncRNA H19 be a therapeutic target for restenosis?
Yes, the findings suggest that inhibiting lncRNA H19 or modulating the miR-125a-3p/FLT1 axis may offer a novel therapeutic strategy to prevent vascular restenosis after angioplasty or stenting.
What experimental models were used in this study?
The study utilized a mouse carotid ligation model for in vivo experiments and human vascular smooth muscle cells (VSMCs) for in vitro experiments to investigate the molecular mechanisms.
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