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DNMT1 Methylation of LncRNA GAS5 Leads to Cardiac Fibroblast Pyroptosis via Affecting NLRP3 Axis

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Abstract

Cell death and inflammation play critical roles in cardiac fibrosis. During the fibrosis process, inflammation and tissue injury were triggered; however, the mechanisms initiating cardiac fibrosis and driving fibroblast pyroptosis remained largely unknown. In this study, we identified long non-coding RNA (LncRNA)-GAS5 as the key onset of cardiac fibroblast pyroptosis and cardiac fibrosis. Here, we detected ISO-induced cardiac fibrosis models and cardiac fibroblast pyroptosis model by stimulating with LPS. We found that the expression of pyroptosis-related proteins such as caspase 1, NLRP3, and DNMT1 was increased in cardiac fibrosis tissue, while the expression of GAS5 was decreased. The overexpressing of LncRNA GAS5 was shown to increase and inhibit cardiac fibroblast pyroptosis, as well as attenuate caspase 1 and NLRP3 expression in cardiac fibroblast. However, the silencing of GAS5 was also observed; it shows the opposite situation. Furthermore, further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine, or downregulation of DNMT1 led to increased GAS5 expression by reversion of promoter hypermethylation in cardiac fibroblast. Importantly, we have demonstrated that DNMT1 methylation of LncRNA GAS5 leads to cardiac fibroblast pyroptosis via affecting NLRP3 axis. Our findings indicate a new regulatory mechanism for cardiac fibroblast pyroptosis under LPS stress, providing a novel therapeutic target for cardiac fibrosis.

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Funding

This project was supported by the National Natural Science Foundation of China (81700212, 81570295), Natural Science Foundation of Anhui Provincial (1808085MH231), Natural Science Foundation of Jiangsu Provincial (BK20191503), and Science Foundation of Anhui Provincial Institute of Cardiovascular Research (KF2018011).

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  1. Qian She and Peng Shi contributed equally to this work.

Authors and Affiliations

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

    Qian She, Peng Shi, Sheng-Song Xu, Hui Tao & Kai-Hu Shi

  2. Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China

    Qian She & Yan Yang

  3. Department of Cardiology, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, China

    Hai-Yang Xuan

  4. Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China

    Kai-Hu Shi

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  1. Qian She
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Correspondence to Hui Tao, Kai-Hu Shi or Yan Yang.

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She, Q., Shi, P., Xu, SS. et al. DNMT1 Methylation of LncRNA GAS5 Leads to Cardiac Fibroblast Pyroptosis via Affecting NLRP3 Axis. Inflammation 43, 1065–1076 (2020). https://doi.org/10.1007/s10753-020-01191-3

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