Harbin Medical University, Harbin, Heilongjiang 150001, China; Department of Cardiology, the fourth affiliated hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
Harbin Medical University, Harbin, Heilongjiang 150001, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Aug;1870(6):167267. doi: 10.1016/j.bbadis.2024.167267. Epub 2024 May 27.
Small non-coding ribonucleic acids (sncRNAs) play an important role in cell regulation and are closely related to the pathogenesis of heart diseases. However, the role and molecular mechanism of transfer RNA-derived small RNAs (tsRNAs) in myocardial fibrosis after myocardial infarction (MI) remain unknown. In this study, we identified and validated sncRNAs (mainly miRNA and tsRNA) associated with myocardial fibrosis after MI through PANDORA sequencing of rat myocardial tissue. As a key enzyme of N4-acetylcytidine (ac4C) acetylation modification, N-acetyltransferase 10 (NAT10) plays an important role in regulating messenger RNA (mRNA) stability and translation efficiency. We found that NAT10 is highly expressed in infarcted myocardial tissue, and the results of acetylated RNA immunoprecipitation sequencing (acRIP-seq) analysis suggest that early growth response 3 (EGR3) may be an important molecule in the pathogenesis of NAT10-mediated myocardial fibrosis. Both in vivo and in vitro experiments have shown that inhibition of NAT10 can reduce the expression of EGR3 and alleviate myocardial fibrosis after MI. tsRNA can participate in gene regulation by inhibiting target genes. The expression of tsr007330 was decreased in myocardial infarction tissue. We found that overexpression of tsr007330 in rat myocardial tissue could antagonize NAT10, improve myocardial function in MI and alleviate myocardial fibrosis. In conclusion, tsRNAs (rno-tsr007330) may regulate the occurrence of myocardial fibrosis by regulating NAT10-mediated EGR3 mRNA acetylation. This study provides new insights into the improvement of myocardial fibrosis after MI by targeting tsRNA therapy.
小非编码核糖核酸（sncRNA）在细胞调控中发挥重要作用，与心脏病的发病机制密切相关。然而，转移 RNA 衍生的小 RNA（tsRNA）在心肌梗死后心肌纤维化中的作用和分子机制尚不清楚。在这项研究中，我们通过对大鼠心肌组织的 PANDORA 测序，鉴定和验证了与心肌梗死后心肌纤维化相关的 sncRNA（主要是 miRNA 和 tsRNA）。N-乙酰转移酶 10（NAT10）作为 N4-乙酰胞嘧啶（ac4C）乙酰化修饰的关键酶，在调节信使 RNA（mRNA）稳定性和翻译效率方面发挥着重要作用。我们发现 NAT10 在梗死心肌组织中高表达，乙酰化 RNA 免疫沉淀测序（acRIP-seq）分析结果表明，早期生长反应 3（EGR3）可能是 NAT10 介导心肌纤维化发病机制中的重要分子。体内和体外实验均表明，抑制 NAT10 可降低 EGR3 的表达，减轻心肌梗死后的心肌纤维化。tsRNA 可以通过抑制靶基因参与基因调控。tsr007330 在心肌梗死组织中的表达减少。我们发现，tsr007330 在大鼠心肌组织中的过表达可以拮抗 NAT10，改善 MI 中的心肌功能并减轻心肌纤维化。总之，tsRNA（rno-tsr007330）可能通过调节 NAT10 介导的 EGR3 mRNA 乙酰化来调节心肌纤维化的发生。本研究为通过靶向 tsRNA 治疗改善心肌梗死后心肌纤维化提供了新的思路。
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