Zuo Tongkun, Tang Qing, Zhang Xiangcheng, Shang Futai
ICU, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an 223300, P.R. China.
Mol Ther Nucleic Acids. 2020 Jul 25;22:273-284. doi: 10.1016/j.omtn.2020.07.031. eCollection 2020 Dec 4.
Mitochondrial dysfunction and chemokine production have been reported to be involved in the pathogenesis of sepsis. Our initial bioinformatics analysis identified differentially expressed TLR2 in sepsis and the upstream regulatory microRNA-410-3p (miR-410-3p). Hence, the current study was performed to characterize the potential mechanism by which miR-410-3p modulates mitochondrial dysfunction and chemokine production in lipopolysaccharide (LPS)-induced mice and cardiomyocytes . Next, we identified that miR-410-3p was downregulated, while TLR2 was upregulated in LPS-induced mice and cardiomyocytes. In addition, miR-410-3p was confirmed to target and inhibit the TLR2 expression. Thereafter, gain- or loss-of-function experiments were conducted to investigate the effect of miR-410-3p and TLR2 on mitochondrial function and chemokine production. TLR2 knockdown or miR-410-3p overexpression was found to alleviate mitochondrial membrane damage and mitochondrial swelling, in addition to augmenting the levels of adenosine triphosphate, mitochondrial membrane potential, and the expression levels of CCL7, CCL5, CXCL1, and CXCL9 and . In conclusion, miR-410-3p-mediated TLR2 inhibition alleviated mitochondrial dysfunction and reduced chemokine production in LPS-induced experimental sepsis. Therefore, the overexpression of miR-410-3p may represent a potential strategy for the treatment of sepsis-induced myocardial injury.
据报道，线粒体功能障碍和趋化因子产生与脓毒症的发病机制有关。我们最初的生物信息学分析确定了脓毒症中差异表达的Toll样受体2（TLR2）以及上游调控微小RNA-410-3p（miR-410-3p）。因此，本研究旨在阐明miR-410-3p调节脂多糖（LPS）诱导的小鼠和心肌细胞中线粒体功能障碍和趋化因子产生的潜在机制。接下来，我们发现miR-410-3p在LPS诱导的小鼠和心肌细胞中表达下调，而TLR2表达上调。此外，证实miR-410-3p靶向并抑制TLR2的表达。此后，进行了功能获得或缺失实验，以研究miR-410-3p和TLR2对线粒体功能和趋化因子产生的影响。结果发现，敲低TLR2或过表达miR-410-3p除了能提高三磷酸腺苷水平、线粒体膜电位以及CCL7、CCL5、CXCL1和CXCL9的表达水平外，还能减轻线粒体膜损伤和线粒体肿胀。总之，miR-410-3p介导的TLR2抑制减轻了LPS诱导的实验性脓毒症中的线粒体功能障碍并减少了趋化因子的产生。因此，miR-410-3p的过表达可能是治疗脓毒症诱导的心肌损伤的一种潜在策略。
