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A-to-I编辑的miR-411通过靶向TGFBR2和CD44减轻梗死后心脏纤维化

A-to-I RNA editing of miR-411 attenuates post-infarction cardiac fibrosis via dual targeting of TGFBR2 and CD44

    摘要
  • 摘要:
    目的 探讨小非编码RNA序列上的A-to-I 编辑在心肌梗死（简称心梗）后心脏纤维化过程中的作用及治疗潜力。
    方法  结合GEO数据库和课题组自有的心梗小鼠模型RNA-seq数据，从心梗不同阶段的RNA-seq数据出发，全基因组分析识别位于小非编码RNA序列的A-to-I RNA 编辑。在心梗后1 d到8周不同时间点的进程中，有4个miRNA上发生了在对照组和心梗组具有比例差异的A-to-I RNA 编辑位点。其中，miR-411种子区第4核苷酸的A-to-I编辑比例随心梗进程显著升高（P＜0.01）。后续测序验证证实miR-411种子区该位点的A-to-I编辑发生在小鼠心梗模型及心力衰竭患者中。
    结果  miR-411种子区第4核苷酸的A-to-I编辑比例变化主要发生在心肌成纤维细胞而非心肌细胞中，该位点的编辑依赖ADAR2而非ADAR1。与野生型miR-411（WT-miR-411）相比，编辑后的miR-411（ED-miR-411）在心脏成纤维细胞中显示出胶原相关通路例如细胞外基质（extracellular matrix，ECM）受体相互作用、含胶原的ECM和ECM组织的抑制能力（P＜0.01）。机制上，双荧光素酶实验证实ED-miR-411直接靶向转化生长因子β受体2型（type Ⅱ transforming growth factor-beta receptor，TGFBR2）和CD44的3′UTR，并抑制其表达，二者是TGF-β介导成纤维细胞活化的关键驱动因子。ED-miR-411过表达可抑制TGF-β诱导的胶原合成和成纤维细胞增殖（P＜0.05）。在体内实验中，心梗后1周心肌内注射ED-miR-411模拟物可使纤维化减少约40%，射血分数提高15%（与对照组相比，P＜0.01），而WT-miR-411无治疗作用。
    结论  miR-411的A-to-I编辑通过抑制TGFBR2和CD44，成为内源性抗纤维化机制，从而阻断TGF-β信号和ECM失调。本研究提示ED-miR-411可能是一种新型RNA疗法候选分子，可减轻梗死后心脏重塑。

     

    Abstract:
    Objective To explore the functional impact of A-to-I editing in the seed region of miR-411 during post-myocardial infarction (MI) fibrosis and elucidate its therapeutic potential.
    Methods Integrating GEO database with myocardial RNA-seq data from MI mouse models, we identified dynamic A-to-I RNA editing in small noncoding RNAs across MI progression (1 day to 8 weeks post-MI). Four miRNAs exhibited differential editing rates between MI and controls, with miR-411 showing progressive editing enhancement at seed region position 4 (P＜0.01). This editing event was validated in both murine MI models and human heart failure specimens.
    Results  The A-to-I editing ratio change of the 4th nucleotide in the seed region of miR-411 mainly occurs in cardiac fibroblasts rather than cardiomyocytes, and the editing at this site depends on ADAR2 rather than ADAR1. Edited miR-411 (ED-miR-411) diverged from wild-type miR-411 (WT-miR-411) in suppressing collagen-related pathways (extracellular matrix ECM-receptor interaction, collagen-containing ECM, ECM organization; P＜0.01) in cardiac fibroblasts. Mechanistically, dual-luciferase assays confirmed ED-miR-411 directly targeted the 3′UTR and suppressed expression of type Ⅱ transforming growth factor (TGF)-beta receptor (TGFBR2) and CD44, which were key drivers of TGF-β-mediated fibroblast activation. ED-miR-411 overexpression blunted TGF-β-induced collagen synthesis and myofibroblast proliferation (P＜0.05). In vivo, intramyocardial delivery of ED-miR-411 mimics at 1 week post-MI reduced fibrosis by 40% and improved ejection fraction by 15% (P＜0.01 vs controls), whereas WT-miR-411 showed no therapeutic effect.
    Conclusions A-to-I editing of miR-411 emerges as an endogenous anti-fibrotic mechanism by repressing TGFBR2 and CD44, thereby disrupting TGF-β signaling and ECM dysregulation. Our findings highlight ED-miR-411 as a novel RNA-based therapeutic candidate to mitigate post-infarction cardiac remodeling.

     

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