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N-甲基腺苷（mA）甲基转移酶METTL3通过依赖IGF2BP1/HDAC4的方式调节脓毒症诱导的心肌损伤。

N-methyladenosine (mA) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner.

作者信息

Shen Hao, Xie Keliang, Li Miaomiao, Yang Qianyu, Wang Xiaoye

机构信息

Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Department of Pediatric surgery, Tianjin Children's Hospital, Tianjin, 300074, China.

出版信息

Cell Death Discov. 2022 Jul 15;8(1):322. doi: 10.1038/s41420-022-01099-x.

DOI:10.1038/s41420-022-01099-x
PMID:35840562
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9287338/
Abstract

Recent studies have identified that N-methyladenosine (mA) extensively participates in the myocardial injury pathophysiological process. However, the role of mA on sepsis-induced myocardial injury is still unclear. Here, we investigated the functions and mechanism of mA methyltransferase METTL3 for septic myocardial injury. Results illustrated that the mA modification level and METTL3 up-regulated in the lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2 cells). Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed the mA profile of the septic myocardial injury cellular model. Functionally, METTL3 knockdown repressed the inflammatory damage of cardiomyocytes induced by LPS. Mechanistically, we found that HDAC4 had remarkable mA modification sites on its 3'-UTR genome, acting as the downstream target of METTL3. Besides, mA reader IGF2BP1 recognized the mA modification sites on HDAC4 mRNA and enhanced its RNA stability. In conclusion, the findings illustrated a role of METTL3/IGF2BP1/mA/HDAC4 axis on sepsis-induced myocardial injury, which might provide novel therapeutic strategy for septic myocardial injury.

摘要

最近的研究表明，N-甲基腺苷（mA）广泛参与心肌损伤的病理生理过程。然而，mA在脓毒症诱导的心肌损伤中的作用仍不清楚。在此，我们研究了mA甲基转移酶METTL3在脓毒症性心肌损伤中的功能和机制。结果表明，在脂多糖（LPS）诱导的心肌细胞（H9C2细胞）中，mA修饰水平和METTL3上调。甲基化RNA免疫沉淀测序（MeRIP-Seq）揭示了脓毒症性心肌损伤细胞模型的mA图谱。在功能上，敲低METTL3可抑制LPS诱导的心肌细胞炎症损伤。机制上，我们发现HDAC4在其3'-UTR基因组上有显著的mA修饰位点，是METTL3的下游靶点。此外，mA阅读器IGF2BP1识别HDAC4 mRNA上的mA修饰位点并增强其RNA稳定性。总之，这些发现阐明了METTL3/IGF2BP1/mA/HDAC4轴在脓毒症诱导的心肌损伤中的作用，这可能为脓毒症性心肌损伤提供新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/4ebe049cd1bc/41420_2022_1099_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/fb62b684948a/41420_2022_1099_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/352d9a31d523/41420_2022_1099_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/3be95ebf9483/41420_2022_1099_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/dc21c71784ca/41420_2022_1099_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/4ebe049cd1bc/41420_2022_1099_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/fb62b684948a/41420_2022_1099_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/352d9a31d523/41420_2022_1099_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/3be95ebf9483/41420_2022_1099_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/dc21c71784ca/41420_2022_1099_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1d2/9287338/4ebe049cd1bc/41420_2022_1099_Fig5_HTML.jpg

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