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

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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Acknowledgments

Thanks to all the participators.

Author information

Correspondence to Jun Feng.

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The authors declare that they have no conflict of interest.

Additional information

Editor: Tetsuji Okamoto

Electronic supplementary material

Figure S1
figure5

(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 (2020) doi:10.1007/s11626-019-00419-3

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Keywords

  • Cardiac hypertrophy
  • MiR-4458
  • NRF1
  • TFAM
  • TTP