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Dihydroartemisinin inhibits restenosis after balloon angioplasty via circHSPA4/miR-19a-5p axis

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Abstract

Dihydroartemisinin (DHA) inhibits restenosis following balloon angioplasty. However, data on the mechanisms of DHA activity in restenosis remains scant. Here, we investigated the role of circRNAs in mediating the inhibitory activity of DHA in neointimal formation. We used total RNA sequencing data to profile the expression of mRNA, circRNA and small RNA in sham, vascular balloon injury (VBI) and DHA-treated groups. CCK8 and EdU assays were employed to analyze cell proliferation, while qRT-PCR and Western blot were used to analyze the RNA or protein expression. In addition, we used RNA immunoprecipitation and luciferase reporter assay to assess the binding of circHSPA4 with miR-19a-5p. RNA sequencing demonstrated that circHSPA4 was upregulated in VBI. Treatment with DHA effectively suppressed the upregulation of the circHSPA4. In addition, analysis of platelet-derived growth family factor bb (PDGFbb)-induced HA-VSMCs showed upregulation of circHSPA4, which was associated with cell proliferation and differentiation. CircHSPA4 was shown to induce dedifferentiation and proliferation of smooth muscle cells. PDGFBB-induced overexpression of CircHSPA4 in HA-VSMCs led to suppression of miR-19a-5p, a phenomenon that was reversed by DHA, in concentration-dependent fashion. In addition, miR-19a-5p reduced the dedifferentiation and proliferation of the smooth muscle cells. Our data demonstrated that CircHSPA4 regulates proliferation and differentiation of smooth muscle cells. DHA and miR-19a-5p modulates CircHSPA4 and can be used as coated drugs on balloon catheter to improve the success rate of vascular remodeling.

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Funding

This work was supported by the Heilongjiang Provincial Natural Science Foundation of China (LH2020H035); the Fundamental Research Funds for the Provincial University (2019-KYYWF-0343); the open Fund of Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China (GPKF202001); Heilongjiang Postdoctoral Scientific Research Developmental Fund (LBH-Q20143); and Special supported scientific research project of the Fourth Affiliated Hospital of Harbin Medical University (HYDSYTB202101).

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Authors and Affiliations

  1. Department of General Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang, 150001, Harbin, China

    Renping Huang

  2. Department of Immunology, Harbin Medical University, Heilongjiang, 150001, Harbin, China

    Wenjing Xing

  3. Department of Ophthalmology, The First Affiliated Hospital, Harbin Medical University, Heilongjiang, 150001, Harbin, China

    Xiaoyuan Wang

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  1. Renping Huang
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Contributions

HR designed, analyzed and interpreted the experiments, performed the VBI model in vivo and wrote the manuscript. XW performed cell culture, cell behavior experiments and the VBI model in vivo assays. WX led the study, supervised the overall project and reviewed the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Xiaoyuan Wang.

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Huang, R., Xing, W. & Wang, X. Dihydroartemisinin inhibits restenosis after balloon angioplasty via circHSPA4/miR-19a-5p axis. Mol Cell Biochem 479, 951–961 (2024). https://doi.org/10.1007/s11010-023-04778-0

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