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NRF1-enhanced miR-4458 alleviates cardiac hypertrophy through releasing TTP-inhibited TFAM

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Abstract

Growing evidence suggests the crucial role of microRNAs (miRNAs) in regulating basic cell functions, and therefore participating in the pathologic development of diverse human diseases, including cardiac hypertrophy. Herein, we explained that miR-4458 was distinctly stimulated in Ang II-stimulated hypertrophic H9c2 cells. Intriguingly, miR-4458 inhibition led to exacerbated hypertrophic phenotypes in Ang II-treated H9c2 cells. In addition, the compensatory upregulation of miR-4458 in Ang II-treated H9c2 cells was ascribed to its transcriptional enhancement by NRF1, a transcription factor previously identified to be activated in early cardiac hypertrophy. Moreover, we discovered that miR-4458 served as a negative modulator in cardiac hypertrophy by prompting TFAM, a well-recognized myocardial protective protein. TTP, a RBP that always leads to degradation of recognized mRNAs, was predicted to interact with both miR-4458 and TFAM mRNA. Importantly, we verified that miR-4458 facilitated TFAM expression in cardiomyocytes by directly targeting TTP and releasing TTP-destabilized TFAM mRNA. On the whole, these findings demonstrated that NRF1-induced miR-4458 boosted TFAM via targeting TTP to dampen the exacerbation of cardiac hypertrophy, which indicates miR-4458 as a promising biomarker for the cardiac hypertrophy treatment.

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References

  • Aaronson KD, Sackner-Bernstein J (2006) Risk of death associated with nesiritide in patients with acutely decompensated heart failure. Jama 296:1465–1466

    Article  CAS  Google Scholar 

  • Anant S, Houchen CW (2009) HuR and TTP: two RNA binding proteins that deliver message from the 3' end. Gastroenterology 136:1495–1498

    Article  Google Scholar 

  • Barry SP, Townsend PA (2010) What causes a broken heart—molecular insights into heart failure. Int Rev Cell Mol Biol 284:113–179

    Article  CAS  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  Google Scholar 

  • Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5:396–400

    Article  CAS  Google Scholar 

  • Bartz RR, Suliman HB, Piantadosi CA (2015) Redox mechanisms of cardiomyocyte mitochondrial protection. Front Physiol 6:291

    Article  Google Scholar 

  • Bhawe K, Roy D (2018) Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression. Cell Oncol (Dordr) 41:465–484. https://doi.org/10.1007/s13402-018-0395-3

    Article  CAS  Google Scholar 

  • Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, Chen JF, Deng Z, Gunn B, Shumate J, Willis MS, Selzman CH, Wang DZ (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119:2772–2786

    Article  CAS  Google Scholar 

  • Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Høydal M, Autore C, Russo MA, Dorn GW, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13:613–618

    Article  Google Scholar 

  • Cirillo D, Marchese D, Agostini F, Livi CM, Botta-Orfila T, Tartaglia GG (2014) Constitutive patterns of gene expression regulated by RNA-binding proteins. Genome Biol 15:R13

    Article  Google Scholar 

  • Divakaran V, Mann DL (2008) The emerging role of microRNAs in cardiac remodeling and heart failure. Circ Res 103:1072–1083

    Article  CAS  Google Scholar 

  • Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S, Giacca M (2012) Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492:376–381

    Article  CAS  Google Scholar 

  • Flemming A (2014) Heart failure: targeting miRNA pathology in heart disease. Nat Rev Drug Discov 13:336

    Article  Google Scholar 

  • Greco CM, Condorelli G (2015) Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol 12:488–497

    Article  CAS  Google Scholar 

  • Guo J, Qu H, Chen Y, Xia J (2017) The role of RNA-binding protein tristetraprolin in cancer and immunity. Med Oncol 34:196

    Article  Google Scholar 

  • Heymans S, Corsten MF, Verhesen W, Carai P, van Leeuwen RE, Custers K, Peters T, Hazebroek M, Stöger L, Wijnands E, Janssen BJ, Creemers EE, Pinto YM, Grimm D, Schürmann N, Vigorito E, Thum T, Stassen F, Yin X, Mayr M, de Windt LJ, Lutgens E, Wouters K, de Winther MP, Zacchigna S, Giacca M, van Bilsen M, Papageorgiou AP, Schroen B (2013) Macrophage microRNA-155 promotes cardiac hypertrophy and failure. Circulation 128:1420–1432

    Article  CAS  Google Scholar 

  • Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358:1370–1380

    Article  CAS  Google Scholar 

  • Ho YL, Wu CC, Lin LC, Huang CH, Chen WJ, Chen MF, Liau CS, Lee YT (1998) Assessment of the coronary artery disease and systolic dysfunction in hypertensive patients with the dobutamine-atropine stress echocardiography: effect of the left ventricular hypertrophy. Cardiology 89:52–58

    Article  CAS  Google Scholar 

  • Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, Fujiwara T, Hamasaki N, Takeshita A, Sunagawa K, Tsutsui H (2005) Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 112:683–690

    Article  CAS  Google Scholar 

  • Jing Q, Huang S, Guth S, Zarubin T, Motoyama A, Chen J, Di Padova F, Lin SC, Gram H, Han J (2005) Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120:623–634

    Article  CAS  Google Scholar 

  • Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11:441–450

    Article  CAS  Google Scholar 

  • Kunkel GH, Chaturvedi P, Theilen N, Nair R, Tyagi SC (2017) Mechanism of TFAM mediated cardiomyocyte protection. Can J Physiol Pharmacol. https://doi.org/10.1139/cjpp-2016-0718

    Article  CAS  Google Scholar 

  • Kuppusamy KT, Sperber H, Ruohola-Baker H (2013) MicroRNA regulation and role in stem cell maintenance, cardiac differentiation and hypertrophy. Curr Mol Med 13:757–764

    Article  CAS  Google Scholar 

  • Liu CH, Lv DS, Li M, Sun G, Zhang XF, Bai Y (2017) MicroRNA-4458 suppresses the proliferation of human lung cancer cells in vitro by directly targeting Lin28B. Acta Pharmacol Sin 38:1297–1304. https://doi.org/10.1038/aps.2017.73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Li N, Long B, Fan YY, Liu CY, Zhou QY, Murtaza I, Wang K, Li PF (2014) Cardiac hypertrophy is negatively regulated by miR-541. Cell Death Dis 5:e1171–e1171

    Article  CAS  Google Scholar 

  • Liu X, Wang J, Zhang G (2019) miR-4458 regulates cell proliferation and apoptosis through targeting SOCS1 in triple-negative breast cancer. J Cell Biochem. https://doi.org/10.1002/jcb.28565

    Article  CAS  Google Scholar 

  • McKinsey TA, Kass DA (2007) Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov 6:617–635

    Article  CAS  Google Scholar 

  • Nomura S, Satoh M, Fujita T, Higo T, Sumida T, Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M, Fujita K, Harada M, Toko H, Kobayashi Y, Ito K, Takimoto E, Akazawa H, Morita H, Aburatani H, Komuro I (2018) Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. Nat Commun 9:4435

    Article  Google Scholar 

  • Qin Y, Cheng C, Lu H, Wang Y (2016) miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells. Biochem Biophys Res Commun 469:37–43

    Article  CAS  Google Scholar 

  • Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. https://doi.org/10.1038/nrd.2016.246

    Article  CAS  Google Scholar 

  • Seok HY, Chen J, Kataoka M, Huang ZP, Ding J, Yan J, Hu X, Wang DZ (2014) Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res 114:1585–1595

    Article  CAS  Google Scholar 

  • Tang D, Sun B, Yu H, Yang Z, Zhu L (2015) Tumor-suppressing effect of miR-4458 on human hepatocellular carcinoma. Cell Physiol Biochem 35:1797–1807

    Article  CAS  Google Scholar 

  • Ucar A, Gupta SK, Fiedler J, Erikci E, Kardasinski M, Batkai S, Dangwal S, Kumarswamy R, Bang C, Holzmann A, Remke J, Caprio M, Jentzsch C, Engelhardt S, Geisendorf S, Glas C, Hofmann TG, Nessling M, Richter K, Schiffer M, Carrier L, Napp LC, Bauersachs J, Chowdhury K, Thum T (2012) The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun 3:1078–1078

    Article  Google Scholar 

  • Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524

    Article  CAS  Google Scholar 

  • van Rooij E, Olson EN (2007) MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J Clin Invest 117:2369–2376

    Article  Google Scholar 

  • van Rooij E, Olson EN (2012) MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov 11:860–872

    Article  Google Scholar 

  • Wang J, Song Y, Zhang Y, Xiao H, Sun Q, Hou N, Guo S, Wang Y, Fan K, Zhan D, Zha L, Cao Y, Li Z, Cheng X, Zhang Y, Yang X (2012) Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice. Cell Res 22:516–527

    Article  CAS  Google Scholar 

  • Wang J, Yang X (2012) The function of miRNA in cardiac hypertrophy. Cell Mol Life Sci 69:3561–3570

    Article  CAS  Google Scholar 

  • Yan M, Chen C, Gong W, Yin Z, Zhou L, Chaugai S, Wang DW (2014) miR-21-3p regulates cardiac hypertrophic response by targeting histone deacetylase-8. Cardiovasc Res. https://doi.org/10.1093/cvr/cvu254

    Article  Google Scholar 

  • Yang KC, Yamada KA, Patel AY, Topkara VK, George I, Cheema FH, Ewald GA, Mann DL, Nerbonne JM (2014) Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129:1009–1021

    Article  CAS  Google Scholar 

  • Zhang M, Jiang Y, Guo X, Zhang B, Wu J, Sun J, Liang H (2019a) Long non-coding RNA cardiac hypertrophy-associated regulator governs cardiac hypertrophy via regulating miR-20b and the downstream PTEN/AKT pathway. https://doi.org/10.1111/jcmm.14641

    Article  CAS  Google Scholar 

  • Zhang Q, Wang F, Wang F, Wu N (2019b) Long noncoding RNA MAGI1-IT1 regulates cardiac hypertrophy by modulating miR-302e/DKK1/Wnt/beta-catenin signaling pathway. J Cell Physiol. https://doi.org/10.1002/jcp.28964

    Article  Google Scholar 

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Acknowledgments

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Author notes

  1. Atsuko Hamada, Eri Akagi and Sachiko Yamasaki contributed equally to this work

Authors and Affiliations

  1. Department of Cardiology, The Second People’s Hospital in Hefei City, Hefei, 241000, China

    Mengsi Yang, Jing Zhang, Xiaoqin Jin, Chao Li, Gaoliang Zhou & Jun Feng

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  1. Mengsi Yang
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  2. Jing Zhang
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  3. Xiaoqin Jin
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  4. Chao Li
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  5. Gaoliang Zhou
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  6. Jun Feng
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Correspondence to Jun Feng.

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Editor: Tetsuji Okamoto

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Figure S1

(A) ANP, BNP and β-MHC expression in mice model was assessed in qRT-PCR. (B) Western blot assayed ANP, BNP and β-MHC protein in mice model. (C) MiR-4458 expression in mice model was tested in qRT-PCR. (D) NRF1 expression in mice model was examined in qRT-PCR. (E) Overexpression efficacy of TFAM in H9c2 was confirmed via qRT-PCR. (F) Overexpression efficacy of miR-4458 in H9c2 was testified through qRT-PCR. * P < 0.05, ** P < 0.01 (PNG 295 kb)

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Yang, M., Zhang, J., Jin, X. et al. NRF1-enhanced miR-4458 alleviates cardiac hypertrophy through releasing TTP-inhibited TFAM. In Vitro Cell.Dev.Biol.-Animal 56, 120–128 (2020). https://doi.org/10.1007/s11626-019-00419-3

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  • DOI: https://doi.org/10.1007/s11626-019-00419-3

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