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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711848.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts
Authors:Wang, D.; Zhang, H.; Li, M.; Frid, M. G.; Flockton, A. R.; McKeon, B. A.; Yeager, M. E.; Fini, M. A.; Morrell, N. W.; Pullamsetti, S. S.; Velegala, S.; Seeger, W.; McKinsey, T. A.; Sucharov, C. C.; Stenmark, K. R.
Date of Publication (YYYY-MM-DD):2014-01-03
Title of Journal:Circ Res
Volume:114
Issue / Number:1
Start Page:67
End Page:78
Audience:Not Specified
Abstract / Description: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.
Free Keywords:3' Untranslated Regions; Adult; Animals; Cattle; *Cell Movement; *Cell Proliferation; Chemokine CCL2/genetics/metabolism; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism; Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism; Familial Primary Pulmonary Hypertension; Female; Fibroblasts/*metabolism/physiology; Forkhead Transcription Factors/genetics/metabolism; Histone Deacetylases/metabolism; Humans; Hypertension, Pulmonary/genetics/*metabolism/pathology; Inflammation/metabolism; Male; Mice, Inbred C57BL; MicroRNAs/genetics/*metabolism; Phenotype; Polypyrimidine Tract-Binding Protein/genetics/metabolism; Protein Binding; Pulmonary Artery/metabolism/pathology; Rats; Rats, Wistar; Receptor, Notch1/genetics/metabolism; Signal Transduction; Transcription, Genetic; anoxia; hypertension, pulmonary; migration; neoplasms; proliferation
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822045
Identifiers:ISSN:1524-4571 (Electronic) 0009-7330 (Linking) %R 10.1161/CIRCRESAHA.114.301633
URL:http://www.ncbi.nlm.nih.gov/pubmed/24122720
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