MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2
| Autor: | Lei Han, Ruhui Han, Weiwen Yan, Wenxi Yao, Chunhui Ni, Yan Li, Qiuyun Wu, Rong Rong, Jingjin Yang, Xiaoming Ji, Jiali Yuan, Baoli Zhu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Pulmonary Fibrosis Down-Regulation Biology Transforming Growth Factor beta1 Extracellular matrix Mice 03 medical and health sciences Drug Discovery microRNA Pulmonary fibrosis Autophagy medicine Animals Humans Extracellular Signal-Regulated MAP Kinases Lung Genetics (clinical) Base Sequence Cell growth Autophagosomes Fibroblasts Silicon Dioxide medicine.disease Up-Regulation Cell biology Mice Inbred C57BL Disease Models Animal MicroRNAs 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Apoptosis Proteolysis NIH 3T3 Cells Molecular Medicine Myofibroblast |
| Zdroj: | Journal of Molecular Medicine. 94:1267-1279 |
| ISSN: | 1432-1440 0946-2716 |
| Popis: | Silicosis is a fatal pulmonary fibrotic disorder characterized by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. MiR-449a is a potential mediator of many cellular processes, including cell proliferation, differentiation, and apoptosis. We hypothesized that miR-449a may play a crucial role in the progression of pulmonary fibrogenesis. Here, we described miR-449a as a new autophagy-regulated miRNA. Importantly, miR-449a expression was significantly decreased in lung tissues of mice with silica treatment, and it was similarly expressed in NIH-3T3 and MRC-5 cells stimulated with TGF-β1. The activity of autophagy was inhibited in fibrotic lung tissues and TGF-β1-treated fibroblasts. To investigate the potential effect of miR-449a, we overexpressed miR-449a in mouse models and found that miR-449a significantly reduced both the distribution and severity of lung lesions induced by silica. In addition, miR-449a was observed to induce the activity of autophagy in vivo and in vitro. Notably, Bcl2 was identified as a target of miR-449a. Bcl2 levels were decreased in NIH-3T3 cells upon miR-449a overexpression. Indeed, the Bcl2 3' UTR contained functional miR-449a responsive sequences. Furthermore, TGF-β1 was observed to increase the expression of Bcl2 via the MAPK/ERK pathway. These results suggest that miR-449a is an important regulator of autophagy, as well as a novel endogenous suppressor of pulmonary fibrosis.MiR-449a expression was decreased in fibrotic lungs and activated fibroblasts. Autophagy was inhibited in fibrotic lung tissues and TGF-β1-treated fibroblasts. MiR-449a had an antifibrotic effect in silica-induced lung fibrosis. MiR-449a upregulated autophagic activity in vitro. Bcl2 is the autophagy-related target of miR-449a. |
| Databáze: | OpenAIRE |
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