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CircHAT1 regulates the proliferation and phenotype switch of vascular smooth muscle cells in lower extremity arteriosclerosis obliterans through targeting SFRS1

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Abstract

This study aimed to decipher the mechanism of circular ribonucleic acids (circRNAs) in lower extremity arteriosclerosis obliterans (LEASO). First, bioinformatics analysis was performed for screening significantly down-regulated cardiac specific circRNA—circHAT1 in LEASO. The expression of circHAT1 in LEASO clinical samples was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of splicing factor arginine/serine-rich 1 (SFRS1), α-smooth muscle actin (α-SMA), Calponin (CNN1), cyclin D1 (CNND1) and smooth muscle myosin heavy chain 11 (SMHC) in vascular smooth muscle cells (VSMCs) was detected by Western blotting. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2ʹ-deoxyuridine (EdU) and Transwell assays were used to evaluate cell proliferation and migration, respectively. RNA immunoprecipitation (RNA-IP) and RNA pulldown verified the interaction between SFRS1 and circHAT1. By reanalyzing the dataset GSE77278, circHAT1 related to VSMC phenotype conversion was screened, and circHAT1 was found to be significantly reduced in peripheral blood mononuclear cells (PBMCs) of LEASO patients compared with healthy controls. Knockdown of circHAT1 significantly promoted the proliferation and migration of VSMC cells and decreased the expression levels of contractile markers. However, overexpression of circHAT1 induced the opposite cell phenotype and promoted the transformation of VSMCs from synthetic to contractile. Besides, overexpression of circHAT1 inhibited platelet-derived growth factor-BB (PDGF-BB)-induced phenotype switch of VSMC cells. Mechanistically, SFRS1 is a direct target of circHAT1 to mediate phenotype switch, proliferation and migration of VSMCs. Overall, circHAT1 regulates SFRS1 to inhibit the cell proliferation, migration and phenotype switch of VSMCs, suggesting that it may be a potential therapeutic target for LEASO.

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Data availability

The data that support the findings of this study are openly available in GEO database at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE77280 and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL19978.

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Funding

This study has been supported by Guangdong Natural Science Foundation (2021A1515011173); Guangdong Province Medical Science and Technology Research Project (A2020451).

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Author notes

  1. Xian-ying Huang and Fang-yong Fu have contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China

    Xian-ying Huang, Fang-yong Fu, Kai Qian, Qiao-li Feng, Wei-yu Wu, Yuan-lin Luo & Shui-chuan Huang

  2. Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China

    Sai Cao

  3. Department of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong Province, China

    Wei-jie Chen & Zhi Zhang

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  1. Xian-ying Huang
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Contributions

XH and FF conceptualized and designed the study, drafted the initial manuscript. KQ, KQ, SC, WW, YL and WC collected the data and carried out the initial analyses. ZZ and SH critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Zhi Zhang or Shui-chuan Huang.

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The study was made based on the Declaration of Helsinki with the approval by the Research Ethics Committee of Southern Hospital of Southern Medical University.

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Huang, Xy., Fu, Fy., Qian, K. et al. CircHAT1 regulates the proliferation and phenotype switch of vascular smooth muscle cells in lower extremity arteriosclerosis obliterans through targeting SFRS1. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04932-2

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