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
    1 These are co-first authors
    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
    1 These are co-first authors
    Department of Thoracic and Cardiac Surgery, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Xue Yang
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Kun Wang
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Ning Wang
    Department of Cardiovascular, Suqian First Hospital, Suqian 223800, Jiangsu Province, PR China
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  • Ting-Bo Jiang
    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.
    Department of Cardiovascular, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, PR China
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  • Author Footnotes
    1 These are co-first authors


      • 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.



      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.


      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.


      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.


      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


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        • Gopinathannair R.
        • Chen L.Y.
        • Chung M.K.
        • Cornwell W.K.
        • Furie K.L.
        • Lakkireddy D.R.
        • et al.
        Managing atrial fibrillation in patients with heart failure and reduced ejection fraction: a scientific statement from the American Heart Association.
        Circ. Arrhythm. Electrophysiol. 2021; 14e000078
        • Carrick R.T.
        • Maron M.S.
        • Adler A.
        • Wessler B.
        • Hoss S.
        • Chan R.H.
        • et al.
        Development and validation of a clinical predictive model for identifying hypertrophic cardiomyopathy patients at risk for atrial fibrillation: the HCM-AF score.
        Circ. Arrhythm. Electrophysiol. 2021; 14e009796
        • Lu X.
        • Chen T.
        • Liu G.
        • Guo Y.
        • Shi X.
        • Chen Y.
        • et al.
        Relations between left atrial appendage contrast retention and thromboembolic risk in patients with atrial fibrillation.
        J. Thromb. Thrombolysis. 2021; 53: 191-201
        • Muffoletto M.
        • Qureshi A.
        • Zeidan A.
        • Muizniece L.
        • Fu X.
        • Zhao J.
        • et al.
        Toward patient-specific prediction of ablation strategies for atrial fibrillation using deep learning.
        Front. Physiol. 2021; 12: 674106
        • Hu J.
        • Wang X.
        • Cui X.
        • Kuang W.
        • Li D.
        • Wang J.
        Quercetin prevents isoprenaline-induced myocardial fibrosis by promoting autophagy via regulating miR-223-3p/FOXO3.
        Cell Cycle. 2021; : 1-17
        • Zhu D.
        • Yu H.
        • Liu P.
        • Yang Q.
        • Chen Y.
        • Luo P.
        • et al.
        Calycosin modulates inflammation via suppressing TLR4/NF-kappaB pathway and promotes bone formation to ameliorate glucocorticoid-induced osteonecrosis of the femoral head in rat.
        Phytother. Res. 2021; : 1-12
        • De Sensi F.
        • Penela D.
        • Soto-Iglesias D.
        • Berruezo A.
        • Limbruno U.
        Imaging techniques for the study of fibrosis in atrial fibrillation ablation: from molecular mechanisms to therapeutical perspectives.
        J. Clin. Med. 2021; 10
        • Xie B.
        • Chen B.X.
        • Nanna M.
        • Wu J.Y.
        • Zhou Y.
        • Shi L.
        • et al.
        18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in atrial fibrillation: a pilot prospective study.
        Eur. Heart J. Cardiovasc. Imaging. 2021; 23: 102-112
        • Dai H.
        • Zhao N.
        • Liu H.
        • Zheng Y.
        • Zhao L.
        LncRNA nuclear-enriched abundant transcript 1 regulates atrial fibrosis via the miR-320/NPAS2 Axis in atrial fibrillation.
        Front. Pharmacol. 2021; 12: 647124
        • Liu Y.
        • Li Y.F.
        • Liu J.
        • Deng Z.G.
        • Zeng L.
        • Zhou W.B.
        Long noncoding RNA GAS5 targeting miR-221-3p/cyclin-dependent kinase inhibitor 2B Axis regulates follicular thyroid carcinoma cell cycle and proliferation.
        Pathobiology. 2021; : 1-12
        • Hola M.A.M.
        • Ali M.A.M.
        • ElNahass Y.
        • Salem T.A.E.
        • Mohamed M.R.
        Expression and prognostic relevance of long noncoding RNAs CRNDE and AOX2P in adult acute myeloid leukemia.
        Int. J. Lab. Hematol. 2021; 43: 732-742
        • Ren Z.
        • Li C.
        • Gan Y.
        • Liu X.
        • Liang F.
        Long noncoding RNA taurine-up regulated gene 1 for the prognosis of osteosarcoma: a protocol for meta-analysis and bioinformatics analysis.
        Medicine (Baltimore). 2021; 100e26182
        • Liu Y.
        • Hu R.
        • Zhu J.
        • Nie X.
        • Jiang Y.
        • Hu P.
        • et al.
        The lncRNA PAHRF functions as a competing endogenous RNA to regulate MST1 expression by sponging miR-23a-3p in pulmonary arterial hypertension.
        Vasc. Pharmacol. 2021; 106886
        • Du H.
        • Yang L.
        • Zhang H.
        • Zhang X.
        • Shao H.
        LncRNA TUG1 silencing enhances proliferation and migration of ox-LDL-treated human umbilical vein endothelial cells and promotes atherosclerotic vascular injury repairing via the Runx2/ANPEP axis.
        Int. J. Cardiol. 2021; 338: 204-214
        • Cao F.
        • Li Z.
        • Ding W.M.
        • Yan L.
        • Zhao Q.Y.
        LncRNA PVT1 regulates atrial fibrosis via miR-128-3p-SP1-TGF-beta1-Smad axis in atrial fibrillation.
        Mol. Med. 2019; 25: 7
        • Shen C.
        • Kong B.
        • Liu Y.
        • Xiong L.
        • Shuai W.
        • Wang G.
        • et al.
        YY1-induced upregulation of lncRNA KCNQ1OT1 regulates angiotensin II-induced atrial fibrillation by modulating miR-384b/CACNA1C axis.
        Biochem. Biophys. Res. Commun. 2018; 505: 134-140
        • Sun F.
        • Guo Z.
        • Zhang C.
        • Che H.
        • Gong W.
        • Shen Z.
        • et al.
        LncRNA NRON alleviates atrial fibrosis through suppression of M1 macrophages activated by atrial myocytes.
        Biosci. Rep. 2019; 39
        • Jia R.
        • Li T.
        • Wang N.
        Long noncoding RNA HOTAIR functions as ceRNA to regulate MMP2 in paraquat induced lung epithelial-mesenchymal transition.
        Toxicology. 2021; 152891
        • Dai W.
        • Chao X.
        • Li S.
        • Zhou S.
        • Zhong G.
        • Jiang Z.
        Long noncoding RNA HOTAIR functions as a competitive endogenous RNA to regulate Connexin43 remodeling in atrial fibrillation by sponging MicroRNA-613.
        Cardiovasc. Ther. 2020; 2020: 5925342
        • Tan S.
        • Chen J.
        Small interfering-high mobility group A2 attenuates epithelial-mesenchymal transition in thymic cancer cells via the Wnt/beta-catenin pathway.
        Oncol. Lett. 2021; 22: 586
        • Liu T.
        • Gonzalez De Los Santos F.
        • Hirsch M.
        • Wu Z.
        • Phan S.H.
        Non-canonical Wnt signaling promotes myofibroblast differentiation in pulmonary fibrosis.
        Am. J. Respir. Cell Mol. Biol. 2021; 65: 489-499
        • Vallejo D.
        • Lindsay C.B.
        • Gonzalez-Billault C.
        • Inestrosa N.C.
        Wnt5a modulates dendritic spine dynamics through the regulation of Cofilin via small rho GTPase activity in hippocampal neurons.
        J. Neurochem. 2021; 158: 673-693
        • Wang X.
        • Zou Y.
        • Chen Z.
        • Li Y.
        • Pan L.
        • Wang Y.
        • et al.
        Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis.
        Theranostics. 2021; 11: 1249-1268
        • Lin T.
        • Tao J.
        • Chen Y.
        • Zhang Y.
        • Li F.
        • Zhang Y.
        • et al.
        Selenium deficiency leads to changes in renal fibrosis marker proteins and wnt/beta-catenin signaling pathway components.
        Biol. Trace Elem. Res. 2022; 200: 1127-1139
        • Guo F.
        • Yi X.
        • Li M.
        • Fu J.
        • Li S.
        Snail1 is positively correlated with atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease.
        Exp Ther Med. 2017; 14: 4231-4237
        • He X.
        • Sheng J.
        • Yu W.
        • Wang K.
        • Zhu S.
        • Liu Q.
        LncRNA MIR155HG promotes Temozolomide resistance by activating the Wnt/beta-catenin pathway via binding to PTBP1 in glioma.
        Cell. Mol. Neurobiol. 2021; 41: 1271-1284
        • Fang G.
        • Cao W.
        • Chen L.
        • Song S.
        • Li Y.
        • Yuan J.
        • et al.
        Cadherin-11 deficiency mitigates high-fat diet-induced inflammatory atrial remodeling and vulnerability to atrial fibrillation.
        J. Cell. Physiol. 2021; 236: 5725-5741
        • Wu J.
        • Han D.
        • Shi R.
        • Chen M.
        • Sun J.
        • Tian H.
        • et al.
        Identification of atrial fibrillation-associated lncRNAs in atria from patients with rheumatic mitral valve disease.
        Microsc. Res. Tech. 2019; 82: 1136-1144
        • Wang S.
        • Guo N.
        • Li S.
        • He Y.
        • Zheng D.
        • Li L.
        • et al.
        EZH2 dynamically associates with non-coding RNAs in mouse hearts after acute angiotensin II treatment.
        Front. Cardiovasc. Med. 2021; 8: 585691
        • Bai W.W.
        • Tang Z.Y.
        • Shan T.C.
        • Jing X.J.
        • Li P.
        • Qin W.D.
        • et al.
        Up-regulation of paired-related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a.
        J. Cell. Mol. Med. 2020; 24: 2319-2329
        • Sun X.
        • Chen Z.
        Cancer-associated fibroblast-derived CCL5 contributes to cisplatin resistance in A549 NSCLC cells partially through upregulation of lncRNA HOTAIR expression.
        Oncol. Lett. 2021; 22: 696
        • Wang J.
        • Luo X.
        • Cai S.
        • Sun J.
        • Wang S.
        • Wei X.
        Blocking HOTAIR protects human chondrocytes against IL-1beta-induced cell apoptosis, ECM degradation, inflammatory response and oxidative stress via regulating miR-222-3p/ADAM10 axis.
        Int. Immunopharmacol. 2021; 98: 107903
        • Wu J.
        • Jin L.
        • Zhang Y.
        • Duan A.
        • Liu J.
        • Jiang Z.
        • et al.
        LncRNA HOTAIR promotes endometrial fibrosis by activating TGF-beta1/Smad pathway.
        Acta Biochim. Biophys. Sin. Shanghai. 2020; 52: 1337-1347
        • Chung H.K.
        • Xiao L.
        • Jaladanki K.C.
        • Wang J.Y.
        Regulation of paneth cell function by RNA-binding proteins and noncoding RNAs.
        Cells. 2021; 10
        • Ma Y.
        • Han J.
        • Luo X.
        FOXD1-AS1 upregulates FOXD1 to promote oral squamous cell carcinoma progression.
        Oral Dis. 2021; 00: 1-11
        • Yan G.
        • Sun R.
        • Chen Z.
        • Pan X.
        • Sheng Z.
        • Tang C.
        PTBP1 targets ILK to regulate the hypoxia-induced phenotypic transformation of pulmonary artery smooth muscle cells.
        Drug Des. Devel. Ther. 2021; 15: 2025-2033
        • Sheng J.
        • He X.
        • Yu W.
        • Chen Y.
        • Long Y.
        • Wang K.
        • et al.
        p53-targeted lncRNA ST7-AS1 acts AS a tumour suppressor by interacting with PTBP1 to suppress the Wnt/beta-catenin signalling pathway in glioma.
        Cancer Lett. 2021; 503: 54-68
        • Yao X.Y.
        • Liu J.F.
        • Luo Y.
        • Xu X.Z.
        • Bu J.
        LncRNA HOTTIP facilitates cell proliferation, invasion, and migration in osteosarcoma by interaction with PTBP1 to promote KHSRP level.
        Cell Cycle. 2021; 20: 283-297
        • Li J.
        • Chai W.
        • Zhao Z.
        • Zhou Y.
        • Wu Q.
        Long noncoding RNA HOTTIP enhances the fibrosis of lung tissues by regulating the miR7445p/PTBP1 signaling axis.
        Mol. Med. Rep. 2021; 24
        • Li Z.
        • Ye Z.
        • Ma J.
        • Gu Q.
        • Teng J.
        • Gong X.
        MicroRNA133b alleviates doxorubicininduced cardiomyocyte apoptosis and cardiac fibrosis by targeting PTBP1 and TAGLN2.
        Int. J. Mol. Med. 2021; 48
        • Rodriguez-Trillo A.
        • Mosquera N.
        • Pena C.
        • Rivas-Tobio F.
        • Mera-Varela A.
        • Gonzalez A.
        • et al.
        Non-canonical WNT5A signaling through RYK contributes to aggressive phenotype of the rheumatoid fibroblast-like Synoviocytes.
        Front. Immunol. 2020; 11: 555245
        • Chaker D.
        • Mouawad C.
        • Azar A.
        • Quilliot D.
        • Achkar I.
        • Fajloun Z.
        • et al.
        Inhibition of the RhoGTPase Cdc42 by ML141 enhances hepatocyte differentiation from human adipose-derived mesenchymal stem cells via the Wnt5a/PI3K/miR-122 pathway: impact of the age of the donor.
        Stem Cell Res Ther. 2018; 9: 167
        • Sun J.
        • Zhang Q.
        • Liu X.
        • Shang X.
        Downregulation of IFIT3 relieves the inflammatory response and myocardial fibrosis of mice with myocardial infarction and improves their cardiac function.
        Exp. Anim. 2021; 70: 522-531