miR-145 regulates myofibroblast differentiation and lung fibrosis
miR-145 regulates myofibroblast differentiation and lung fibrosis
复制标题
DOI：
10.1096/fj.12-219493
复制
发表时间：
2013-06-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Yang, Shanzhong;Cui, Huachun;Liu, Gang
成纤维细胞表达平滑肌肌动蛋白-α（SMA-α）定义了向肌成纤维细胞的表型转变，并且是这些分化细胞产生收缩力的主要贡献者。虽然SMA-alpha表达的调控一直是许多研究的焦点，但目前关于miRNA调控肺成肌纤维细胞分化以及这些miRNA参与肺纤维化的信息有限。探讨miR-145在肺成肌纤维细胞分化和肺纤维化中的作用。研究了野生型和miR-145（-/-）小鼠。采用肺纤维化模型和细胞培养系统。将miR-145模拟物或抑制剂转染到肺成纤维细胞中。测定肺成纤维细胞的成纤维活性和收缩活性。我们发现miR-145在TGF-β 1相关的肺成纤维细胞中表达上调。与正常人肺相比，特发性肺纤维化患者肺中的miR-145表达也增加。miR-145在肺成纤维细胞中的过表达增加了SMA-α的表达，增强了收缩性，并促进了局灶性和纤维性粘连的形成。相比之下，miR-145缺陷减少TGF-β 1诱导的SMA-α表达。miR-145不影响TGF-β 1的活性，但促进了潜在TGF-β 1的活化。miR-145靶向KLF 4，一种已知的SMA-α表达负调节因子。最后，我们发现miR-145（-/-）小鼠受到博来霉素诱导的肺纤维化的保护。miR-145在肺肌成纤维细胞的分化中起重要作用。miR-145缺陷可保护博来霉素诱导的肺纤维化，这表明miR-145可能是开发治疗病理性纤维化疾病的新疗法的潜在靶点。杨，S.，崔，H.，Xie，N.，美国，Icyuz，M.，班纳吉，S.，安东尼，V. B.，亚伯拉罕，E.，Thannickal，V.J.，Liu，G. miR-145调节肌成纤维细胞分化和肺纤维化。
The expression of smooth muscle actin-alpha (SMA-alpha) by fibroblasts defines phenotypic transition to myofibroblasts and is a primary contributor to contractile force generation by these differentiated cells. Although the regulation of SMA-alpha expression has been the focus of many studies, there is presently only limited information concerning miRNA regulation of lung myofibroblast differentiation and the involvement of these miRNAs in pulmonary fibrosis. To determine the role of miR-145 in regulating lung myofibroblast differentiation and pulmonary fibrosis. Wild-type and miR-145(-/-) mice were studied. Lung fibrosis models and cell culture systems were employed. miR-145 mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic and contractile activities of lung fibroblasts were determined. We found that miR-145 expression is upregulated in TGF-beta 1-reated lung fibroblasts. miR-145 expression is also increased in the lungs of patients with idiopathic pulmonary fibrosis as compared to in normal human lungs. Overexpression of miR-145 in lung fibroblasts increased SMA-alpha expression, enhanced contractility, and promoted formation of focal and fibrillar adhesions. In contrast, miR-145 deficiency diminished TGF-beta 1 induced SMA-alpha expression. miR-145 did not affect the activity of TGF-beta 1, but promoted the activation of latent TGF-beta 1. miR-145 targets KLF4, a known negative regulator of SMA-alpha expression. Finally, we found that miR-145(-/-) mice are protected from bleomycin-induced pulmonary fibrosis. miR-145 plays an important role in the differentiation of lung myofibroblasts. miR-145 deficiency is protective against bleomycin-induced lung fibrosis, suggesting that miR-145 may be a potential target in the development of novel therapies to treat pathological fibrotic disorders.-Yang, S., Cui, H., Xie, N., Icyuz, M., Banerjee, S., Antony, V. B., Abraham, E., Thannickal, V. J., Liu, G. miR-145 regulates myofibroblast differentiation and lung fibrosis.