MiR-22 may Suppress Fibrogenesis by Targeting TGFβR I in Cardiac Fibroblasts
MiR-22 may Suppress Fibrogenesis by Targeting TGFβR I in Cardiac Fibroblasts
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DOI：
10.1159/000453187
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Chen, Xichuang
中科院分区：
文献类型：
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作者：
Hong, Yuan;Cao, Huaming;Chen, Xichuang
背景/目的：心肌梗死后心肌纤维化（MI）已被确定为心力衰竭发展的关键因素，但心肌纤维化的机制尚不清楚。microRNAs （miRNAs）是导致包括心脏纤维化在内的纤维化疾病的新机制。先前的研究表明miR-22可能是一个潜在的靶点。然而，miR-22在心脏纤维化中的作用和机制仍然不明确。因此，本研究探讨了miR-22在心脏纤维化中的影响。方法：小鼠冠状动脉闭塞后7 d，收集用于组织学的组织，进行马尾松三色染色。此外，使用Lipofectamin 2000用miR-22的模拟物和抑制剂转染心脏成纤维细胞，并使用荧光素酶测定试剂盒测量细胞裂解物中的荧光素酶活性。Western blotting检测胶原、α - sma和TGF β RI蛋白表达水平，real - time-PCR检测Col1 α 1、Col3 α 1、miR-22和TGF β RI mRNA表达水平。结果：在本研究中，我们发现永久性结扎左冠状动脉前降支7天后，miR-22动态下调，并伴有显著的胶原沉积。AMO-22抑制miR-22导致Col1 α 1表达增加。Col3 α 1与培养的心脏成纤维细胞的纤维形成。相反，在培养的心脏成纤维细胞中过表达miR-22可显著抑制血管紧张素ii诱导的胶原形成和纤维发生。此外，我们发现TGF β RI是miR-22的直接靶点，TGF β R的下调可能介导了miR-22的抗纤维化作用。结论：我们的数据清楚地表明，miR-22通过抑制TGF β RI在心脏中的表达，作为血管紧张素ii诱导的心脏纤维化的一种新的负调节因子，可能是治疗心脏纤维化的一种新的潜在治疗靶点。(C) 2016，作者：s . Karger AG，巴塞尔出版
Background/Aims: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. Methods: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR-22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagenl, alpha-SMA and TGF beta RI proteins levels, and real time-PCR was employed to measure the Col1 alpha 1, Col3 alpha 1, miR-22 and TGF beta RI mRNA levels. Results: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1 alpha 1. Col3 alpha 1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGF beta RI is a direct target for miR-22, and downregulation of TGF beta R may have mediated the antifibrotic effect of miR-22. Conclusion: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGF beta RI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis. (C) 2016 The Author(s) Published by S. Karger AG, Basel