MicroRNA-130a attenuates cardiac fibrosis after myocardial infarction through TGF-β/Smad signaling by directly targeting TGF-β receptor 1

Cardiac fibrosis is a common pathophysiological change associated with myocardial infarction (MI), and while there is evidence that miR-130a plays an important role in a variety of fibrotic diseases, its role in the cardiac fibrosis during MI is unclear. Our study aimed to assess miR-130a’s ability to modulate cardiac fibrosis post-MI and uncover its potential molecular mechanisms. miR-130a was significantly downregulated in infarcted myocardium and hypoxic cardiac fibroblasts (CFs), whereas TGF-β, α-SMA, collagen 1 (Col-1), and TGF-β receptor 1 (TGFBR1) were upregulated. We transfected mice with AAV-9 carrying miR-130a and found that miR-130a overexpression statistically improved cardiac function and reduced the area of cardiac fibrosis in mice post-MI. Eukaryotic transcriptome sequencing and dual-luciferase reporter assay results verified that Tgfbr1 was a target gene of miR-130a. miR-130a inhibition heightened Col-1, α-SMA, and TGFBR1 expressions and Smad3 phosphorylation levels in CFs; however, these increments were suppressed by the overexpression of miR-130a. Meanwhile, co-transfection with TGFBR1 weakened miR-130a’s ability to inhibit α-SMA and Col-1 expression. These findings suggest that miR-130a exerts antifibrotic properties by directly targeting TGFBR1 to regulate TGF-β/Smad signaling and inhibit the conversion of CFs to myofibroblasts. Thus, miR-130a is a promising therapeutic target for alleviating cardiac fibrosis.心脏纤维化是与心肌梗死（MI）相关的常见病理生理改变。尽管已有证据表明微小RNA-130a（miR-130a）在多种纤维化疾病中发挥重要作用，但其在心肌梗死相关心脏纤维化中的功能仍不明确。本研究旨在评估miR-130a对心肌梗死后心脏纤维化的调控能力，并揭示其潜在分子机制。研究发现，梗死心肌组织与缺氧心肌成纤维细胞（cardiac fibroblasts，CFs）中miR-130a的表达显著下调，而转化生长因子-β（transforming growth factor-β，TGF-β）、α平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）、Ⅰ型胶原（collagen 1，Col-1）及转化生长因子-β受体1（transforming growth factor-β receptor 1，TGFBR1）的表达均显著上调。研究者通过携带miR-130a的腺相关病毒9型（adeno-associated virus 9，AAV-9）转染小鼠，发现miR-130a过表达可显著改善心肌梗死后小鼠的心脏功能，并缩小心脏纤维化区域。真核转录组测序与双荧光素酶报告基因实验结果证实，Tgfbr1是miR-130a的靶基因。在心肌成纤维细胞中，抑制miR-130a可上调Col-1、α-SMA及TGFBR1的表达，并升高Smad3磷酸化水平；而miR-130a过表达可抑制上述指标的升高。同时，共转染TGFBR1可削弱miR-130a对α-SMA与Col-1表达的抑制作用。上述研究结果表明，miR-130a通过直接靶向TGFBR1调控TGF-β/Smad信号通路，抑制心肌成纤维细胞向肌成纤维细胞转化，从而发挥抗纤维化功效。因此，miR-130a是缓解心脏纤维化的潜在治疗靶点。