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DNMT1-Induced miR-152-3p Suppression Facilitates Cardiac Fibroblast Activation in Cardiac Fibrosis

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Abstract

Novel insights into epigenetic control of cardiac fibrosis are now emerging. Cardiac fibroblasts (CFs) activation into myofibroblasts and the production of extracellular matrix (ECM) is the key to cardiac fibrosis development, but the specific mechanism is not fully understood. In the present study, we found that DNMT1 hypermethylation reduces the expression of microRNA-152-3p (miR-152-3p) and promotes Wnt1/β-catenin signaling pathway leading to CFs proliferation and activation. Cardiac fibrosis was produced by ISO, and the ISO was carried out according to the method described. CFs were harvested and cultured from SD neonatal rats and stimulated with TGF-β1. Importantly, DNMT1 resulted in the inhibition of miR-152-3p in activated CFs and both DNMT1 and miR-152-3p altered Wnt/β-catenin downstream protein levels. Over expression of DNMT1 and miR-152-3p inhibitors promotes proliferation of activating CFs. In addition, decreased methylation levels and over expression of miR-152-3p inhibited CFs proliferation. We determined that DNMT1 can methylate to miR-152-3p and demonstrated that expression of miR-152-3p inhibits CFs proliferation by inhibiting the Wnt1/β-catenin pathway. Our results stand out together DNMT1 methylation regulates miR-152-3p to slow the progression of cardiac fibrosis by inhibiting the Wnt1/β-catenin pathway.

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Acknowledgements

This project was supported by National Natural Science Foundation of China (82170236), Key research and development projects of Anhui Province (202104j07020037), and Natural Science Foundation of Anhui Provincial (1808085MH231) and National Natural Science Foundation Incubation Program of the Second Affiliated Hospital of Anhui Medical University (2020GMFY02).

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China

    Sheng-Song Xu & Kai-Hu Shi

  2. Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei, 230601, China

    Hui Tao

  3. Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, China

    Ji-Fei Ding & Peng Shi

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  1. Sheng-Song Xu
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Correspondence to Kai-Hu Shi or Hui Tao.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Review Board of Anhui Medical University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Xu, SS., Ding, JF., Shi, P. et al. DNMT1-Induced miR-152-3p Suppression Facilitates Cardiac Fibroblast Activation in Cardiac Fibrosis. Cardiovasc Toxicol 21, 984–999 (2021). https://doi.org/10.1007/s12012-021-09690-x

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