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LncRNA HOTAIR promotes myocardial fibrosis in atrial fibrillation through binding with PTBP1 to increase the stability of Wnt5a

  • Author Footnotes
    1 These are co-first authors
    Wei Tan
    Footnotes
    1 These are co-first authors
    Affiliations
    Department of Cardiovascular, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, PR China

    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Author Footnotes
    1 These are co-first authors
    Kun Wang
    Footnotes
    1 These are co-first authors
    Affiliations
    Department of Thoracic and Cardiac Surgery, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Xue Yang
    Affiliations
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Kun Wang
    Affiliations
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Ning Wang
    Affiliations
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Ting-Bo Jiang
    Correspondence
    Corresponding author at: Department of Cardiovascular, The First Affiliated Hospital of Soochow University, No.899, Pinghai Road, Gusu District, Suzhou 215000, Jiangsu Province, PR China.
    Affiliations
    Department of Cardiovascular, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, PR China
    Search for articles by this author
  • Author Footnotes
    1 These are co-first authors

      Highlights

      • HOTAIR and Wnt5a expression was elevated in Ang II-caused myocardial fibrosis.
      • HOTAIR/Wnt5a knockdown inhibited Ang II-caused migration and fibrosis of cardiac fibroblasts.
      • HOTAIR bound with PTBP1 to increase the stability and expression of Wnt5a.
      • Wnt5a up-regulation restored the inhibitory effect of HOTAIR depletion on cardiac fibroblast proliferation and migration.
      • HOTAIR knockdown inhibited the progression of AF in vivo by repressing Wnt signaling.

      Abstract

      Background

      Atrial fibrillation (AF) is one of the most common arrhythmia in clinical practice, and atrial fibrosis is the important mediator in AF. LncRNA HOTAIR was reported to be up-regulated in AF, while the underlying mechanism of HOTAIR in AF remains unclear.

      Methods

      In vitro and in vivo AF model was established. qRT-PCR and Western blotting were used to assess the mRNA expression (HOTAIR, Wnt5a and PTBP1) and protein levels (Wnt5a, collagen I/III, α-SMA, CTGF, p-ERK, ERK, p-JNK, and JNK), respectively. MTT, CCK8, transwell assay was used to test cell viability, proliferation and migration, respectively. RIP assay assessed the correlation among HOTAIR, PTBP1 and Wnt5a. The level of α-SMA was detected by immunofluorescence. HE and Masson staining detected the histological changes and fibrosis in mouse heart tissues.

      Results

      Ang II significantly increased the viability of atrial fibroblasts. The levels of HOTAIR and Wnt5a in fibroblasts were up-regulated by Ang II. HOTAIR silencing or Wnt5a significantly inhibited Ang II-induced proliferation, migration and fibrosis in fibroblasts. HOTAIR silencing repressed Wnt5a-mediated ERK and JNK signaling pathway, and Wnt5a partially abolished the effect of HOTAIR silencing on cell proliferation, migration and fibrosis. Meanwhile, HOTAIR could increase the mRNA stability of Wnt5a via recruiting PTBP1. Furthermore, HOTAIR knockdown notably inhibited the fibrosis in heart tissues of AF mice via regulation of Wnt signaling.

      Conclusion

      HOTAIR could promote atrial fibrosis in AF through binding with PTBP1 to increase Wnt5a stability. Our study might shed new insights on exploring new strategies against AF.

      Graphical abstract

      Keywords

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