Transient Receptor Potential Vanilloid channel regulates fibroblast differentiation and airway remodeling by modulating redox signals through NADPH Oxidase 4
| Autor: | Charles K. Thodeti, Kayla Covington, Sabita Pokhrel, Sathwika Thodeti, Nosayba Al-Azzam, Lakshminarayan Reddy Teegala, Ignacio Gavilanes, Sailaja Paruchuri, Samrawit Ghebreigziabher, Tatiana Chachkovskyy |
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| Rok vydání: | 2020 |
| Předmět: |
TRPV4
TRPV Cation Channels lcsh:Medicine Article Gene Knockout Techniques Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Downregulation and upregulation medicine Animals Humans lcsh:Science Fibroblast Multidisciplinary NADPH oxidase biology urogenital system Chemistry lcsh:R NOX4 Cell Differentiation Transforming growth factor beta Fibroblasts Cell biology medicine.anatomical_structure Gene Expression Regulation NADPH Oxidase 4 Ion channels Plasminogen activator inhibitor-1 cardiovascular system biology.protein Airway Remodeling lcsh:Q Reactive Oxygen Species Oxidation-Reduction Proto-Oncogene Proteins c-akt Myofibroblast Cell signalling Signal Transduction |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-66617-2 |
| Popis: | Asthma is characterized by pathological airway remodeling resulting from persistent myofibroblast activation. Although transforming growth factor beta 1 (TGFβ1), mechanical signals, and reactive oxygen species (ROS) are implicated in fibroblast differentiation, their integration is still elusive. We identified that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel mediates lung fibroblast (LF) differentiation and D. farinae-induced airway remodeling via a novel TRPV4-NADPH Oxidase 4 (NOX4) interaction. NOX4-mediated ROS production is essential for TGFβ1-induced LF differentiation via myocardin-related transcription factor-A (MRTF-A) and plasminogen activator inhibitor 1 (PAI-1). Importantly, TRPV4 inhibition prevented TGFβ1-induced NOX4 expression and ROS production. Both TRPV4 and NOX4 are activated by phosphatidylinositol 3-kinase (PI3K) downstream of TGFβ1, and signals from both TRPV4 and Rac are necessary for NOX4 upregulation. Notably, NOX4 expression is higher in fibroblasts derived from asthmatic patients (disease human LF; DHLF) in comparison to non-asthmatics (normal human LF; NHLF). Further, NOX4 expression is up-regulated in the lungs of D.farinae-treated wild type mice (WT) relative to saline-treated WT, which was attenuated in TRPV4 knockout (KO) mice. Our findings suggest that TRPV4 integrates TGFβ1 and ROS signaling through NOX4 and, TRPV4-NOX4 interaction is amenable to target lung remodeling during asthma. |
| Databáze: | OpenAIRE |
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