Tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway
| Autor: | Yan Zhuang, Shigeki Saito, Martina Korfei, Bin Shan, Fayong Luo, Andreas Guenther, Svitlana Danchuk, Joseph A. Lasky |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Protein Expression mTORC1 Biochemistry Idiopathic pulmonary fibrosis Transforming Growth Factor beta Animal Cells Pulmonary fibrosis Phosphoprotein Phosphatases Medicine lcsh:Science Lung Connective Tissue Cells Aged 80 and over TOR Serine-Threonine Kinases Chemical Reactions 3. Good health Physical Sciences Cellular Types Molecular Probe Techniques Bleomycin 03 medical and health sciences Humans RNA Messenger Molecular Biology Techniques Molecular Biology Aged Molecular Biology Assays and Analysis Techniques Ribosomal Protein S6 Kinases lcsh:R Biology and Life Sciences Proteins Fibroblasts medicine.disease respiratory tract diseases Biological Tissue 030104 developmental biology chemistry Multiprotein Complexes lcsh:Q Developmental Biology Vascular Endothelial Growth Factor A 0301 basic medicine Indoles Pulmonary Fibrosis lcsh:Medicine Histone Deacetylase 6 Hydroxamic Acids Phosphatidylinositol 3-Kinases chemistry.chemical_compound Tubulin Medicine and Health Sciences Phosphorylation Post-Translational Modification Mice Knockout Multidisciplinary Cell Death biology Nuclear Proteins Acetylation Animal Models Middle Aged respiratory system Chemistry medicine.anatomical_structure Experimental Organism Systems Connective Tissue Cell Processes Female Anatomy Signal Transduction Research Article Autophagic Cell Death Immunoblotting Mouse Models Mechanistic Target of Rapamycin Complex 1 Research and Analysis Methods Collagen Type I Histone Deacetylases Model Organisms Autophagy Gene Expression and Vector Techniques Animals PI3K/AKT/mTOR pathway business.industry Autophagosomes Cell Biology Transforming growth factor beta HDAC6 Hypoxia-Inducible Factor 1 alpha Subunit Fibrosis Idiopathic Pulmonary Fibrosis biology.protein Cancer research business Proto-Oncogene Proteins c-akt Collagens |
| Zdroj: | PLoS ONE, Vol 12, Iss 10, p e0186615 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. Histone deacetylase 6 (HDAC6) alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-β1-induced EMT (epithelial-mesenchymal transition). However, the role of HDAC6 in pulmonary fibrosis is unknown. Methods HDAC6 expression in IPF and control lungs was assessed by quantitative real-time PCR (qRT-PCR) and immunoblots. Lung fibroblasts were treated with TGF-β1 ± HDAC6 inhibitors (Tubacin, Tubastatin, ACY1215, or MC1568), and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin (oropharyngeal aspiration; single dose) ± Tubastatin (intraperitoneally injection; daily for 21 days), and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type (WT) and knockout (KO) mice were administered bleomycin, and lungs were evaluated in the same manner. Results HDAC6 expression was deregulated in IPF lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-β1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased Akt phosphorylation and increased Akt-PHLPP (PH domain and Leucine rich repeat Protein Phosphatase) association. Tubastatin repressed TGF-β1-induced S6K phosphorylation, HIF-1α expression, and VEGF expression. Tubastatin also repressed TGF-β1-induced inhibition of LC3B-II (a marker of autophagosome formation). In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-β1-induced collagen expression in lung fibroblasts. Conclusions HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-β1-induced collagen expression, by diminishing Akt phosphorylation and regulating downstream targets such as HIF-1α-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates pulmonary fibrosis, by targeting the TGFβ-PI3K-Akt pathway, likely via an HDAC6-independent mechanism. |
| Databáze: | OpenAIRE |
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