TGF-β1 stimulates HDAC4 nucleus-to-cytoplasm translocation and NADPH oxidase 4-derived reactive oxygen species in normal human lung fibroblasts
| Autor: | Rafael E. Gongora Rosero, Yan Zhuang, Shigeki Saito, Weichao Guo, Cecilia G. Sanchez, Fayong Luo, Joseph A. Lasky, Bin Shan |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Physiology Biopsy Active Transport Cell Nucleus Chromosomal translocation Histone Deacetylases Transforming Growth Factor beta1 03 medical and health sciences 0302 clinical medicine Physiology (medical) Pulmonary fibrosis medicine Animals Humans Myofibroblasts Lung Cells Cultured chemistry.chemical_classification Cell Nucleus Reactive oxygen species NADPH oxidase biology NOX4 NADPH Oxidases Cell Differentiation Cell Biology Fibroblasts medicine.disease Molecular biology Actins Idiopathic Pulmonary Fibrosis Rats Repressor Proteins Protein Transport 030104 developmental biology chemistry Cytoplasm NADPH Oxidase 4 030220 oncology & carcinogenesis biology.protein Reactive Oxygen Species Myofibroblast Transforming growth factor Research Article Protein Binding |
| Popis: | Myofibroblasts are important mediators of fibrogenesis; thus blocking fibroblast-to-myofibroblast differentiation (FMD) may be an effective strategy to treat pulmonary fibrosis (PF). Previously, we reported that histone deacetylase 4 (HDAC4) activity is necessary for transforming growth factor-β1 (TGF-β1)-induced human lung FMD. Here, we show that TGF-β1 increases NADPH oxidase 4 (NOX4) mRNA and protein expression in normal human lung fibroblasts (NHLFs) and causes nuclear export of HDAC4. Application of the NOX family inhibitor diphenyleneiodonium chloride reduces TGF-β1-induced HDAC4 nuclear export, expression of the myofibroblast marker α-smooth muscle actin (α-SMA), and α-SMA fiber formation. Inhibition of HDAC4 nucleus-to-cytoplasm translocation using leptomycin B (LMB) had little effect on α-SMA expression but blocked α-SMA fiber formation. A coimmunoprecipitation assay showed that HDAC4 associates with α-SMA. Moreover, LMB abolishes TGF-β1-induced α-SMA fiber formation and cell contraction. Relevant to human pulmonary fibrosis, idiopathic PF specimens showed significantly higher NOX4 RNA expression and scant HDAC4 staining within nuclei of fibroblast foci myofibroblasts. Taken together, these results indicate that reactive oxygen species promote TGF-β1-mediated myofibroblast differentiation and HDAC4 nuclear export. The physical association of HDAC4 with α-SMA suggests that HDAC4 has a role in regulating the α-SMA cytoskeleton arrangement. |
| Databáze: | OpenAIRE |
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