MicroRNA-124 Controls the Proliferative, Migratory, and Inflammatory Phenotype of Pulmonary Vascular Fibroblasts
| Autor: | Hui Zhang, Kurt R. Stenmark, Min Li, Carmen C. Sucharov, Michael E. Yeager, Werner Seeger, Maria G. Frid, Sivareddy Velegala, Daren Wang, Nicholas W. Morrell, Mehdi A. Fini, Soni Savai Pullamsetti, Timothy A. McKinsey, B. Alexandre McKeon, Amanda Flockton |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Cyclin-Dependent Kinase Inhibitor p21 Male Transcription Genetic Physiology Hypertension Pulmonary Inflammation Pulmonary Artery Biology Histone Deacetylases Proinflammatory cytokine Cell Movement microRNA medicine Animals Humans Familial Primary Pulmonary Hypertension Rats Wistar Receptor Notch1 Fibroblast 3' Untranslated Regions Chemokine CCL2 Cell Proliferation Monocyte Forkhead Transcription Factors Fibroblasts medicine.disease Phenotype Pulmonary hypertension Rats Mice Inbred C57BL MicroRNAs medicine.anatomical_structure Cancer research Cattle Female medicine.symptom Signal transduction Cardiology and Cardiovascular Medicine Cyclin-Dependent Kinase Inhibitor p27 Polypyrimidine Tract-Binding Protein Protein Binding Signal Transduction |
| Zdroj: | Circulation Research. 114:67-78 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.114.301633 |
| Popis: | Rationale : Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown. Objective : We hypothesized that aberrant expression of microRNA-124 (miR-124) regulates this activated fibroblast phenotype and sought to determine the signaling pathways through which miR-124 exerts effects. Methods and Results : We detected significant decreases in miR-124 expression in fibroblasts isolated from calves and humans with severe pulmonary hypertension. Overexpression of miR-124 by mimic transfection significantly attenuated proliferation, migration, and monocyte chemotactic protein-1 expression of hypertensive fibroblasts, whereas anti–miR-124 treatment of control fibroblasts resulted in their increased proliferation, migration, and monocyte chemotactic protein-1 expression. Furthermore, the alternative splicing factor, polypyrimidine tract–binding protein 1, was shown to be a direct target of miR-124 and to be upregulated both in vivo and in vitro in bovine and human pulmonary hypertensive fibroblasts. The effects of miR-124 on fibroblast proliferation were mediated via direct binding to the 3′ untranslated region of polypyrimidine tract–binding protein 1 and subsequent regulation of Notch1/phosphatase and tensin homolog/FOXO3/p21Cip1 and p27Kip1 signaling. We showed that miR-124 directly regulates monocyte chemotactic protein-1 expression in pulmonary hypertension/idiopathic pulmonary arterial hypertension fibroblasts. Furthermore, we demonstrated that miR-124 expression is suppressed by histone deacetylases and that treatment of hypertensive fibroblasts with histone deacetylase inhibitors increased miR-124 expression and decreased proliferation and monocyte chemotactic protein-1 production. Conclusions : Stable decreases in miR-124 expression contribute to an epigenetically reprogrammed, highly proliferative, migratory, and inflammatory phenotype of hypertensive pulmonary adventitial fibroblasts. Thus, therapies directed at restoring miR-124 function, including histone deacetylase inhibitors, should be investigated. |
| Databáze: | OpenAIRE |
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