The role of NOX4 in skin fibroblasts
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ABSTRACT:
PROVIDER: PRJNA810981 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18163333.fastq.gz | Fastqsanger.gz | |||
| SRR18163334.fastq.gz | Fastqsanger.gz | |||
| SRR18163335.fastq.gz | Fastqsanger.gz | |||
| SRR18163336.fastq.gz | Fastqsanger.gz | |||
| SRR18163337.fastq.gz | Fastqsanger.gz |
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Project description:Differentiation of fibroblasts to myofibroblasts is governed by the transforming growth factor beta (TGF-β) through a mechanism involving redox signaling and generation of reactive oxygen species (ROS). Myofibroblasts synthesize proteins of the extracellular matrix and display a contractile phenotype. Myofibroblasts are predominant contributors of wound healing and several pathological states, including fibrotic diseases and cancer. Inhibition of the ROS-generating enzyme NADPH oxidase 4 (NOX4) has been proposed to mitigate fibroblast to myofibroblast differentiation and to offer a therapeutic option for the treatment of fibrotic diseases. In this study, we addressed the role of NOX4 in physiological wound healing and in TGF-β-induced myofibroblast differentiation. We explored the phenotypic changes induced by TGF-β in primary skin fibroblasts isolated from Nox4-deficient mice by immunofluorescence, Western blotting and RNA sequencing. Mice deficient for Cyba, the gene coding for p22phox, a key subunit of NOX4 were used for confirmatory experiments as well as human primary skin fibroblasts. In vivo, the wound healing was similar in wild-type and Nox4-deficient mice. In vitro, despite a strong upregulation following TGF-β treatment, Nox4 did not influence skin myofibroblast differentiation. Nevertheless, up-regulation of the mitochondrial protein Ucp2 and the stress-response protein Hddc3, as well as down-regulation of Islr were observed in Nox4-deficient fibroblasts. Altogether, we provide extensive evidence challenging a profibrotic role of NOX4 in skin fibroblasts and show that Nox4 regulates Ucp2 and Hddc3 expression, suggesting the presence of a so far undescribed redox crosstalk between NOX4 and redox homeostasis in fibroblasts.
2023-03-15 | GSE197562 | GEO
Project description:Transcriptomic analysis of cardiomyocytes in NOX4 transgenic mice
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Project description:RNA-seq analysis was performed in samples from WT and NOX4 Knock-out mice after two-thirds Partial Hepatectomy (PH). Transcriptomic analysis through RNA-seq revealed significant changes mainly 24 hours after PH in NOX4-/- mice and support a relevant role for Myc in a node of regulation of proliferation-related genes.
2021-08-05 | GSE181476 | GEO
Project description:Gene expression profiling of mouse articular chondrocytes infected with Ad-C or Ad-Nox4 In this study, we have attempted to explore the effects of Nox4 and have identified numerous genes which are involved in osteoarthritis pathogenesis.
2022-03-01 | GSE146272 | GEO
Project description:Tightly regulated and cell-specific NADPH-oxidases (Nox) represent one of the major sources of reactive oxygen species (ROS) signaling molecules that are involved in tissue development and stem cell self-renewal. We have characterized the role of Nox4 in osteo-progenitors during postnatal bone development. Nox4 expression in bone and ROS generation were increased during early osteoblast differentiation and bone development. Stromal osteoblastic cell self-renewal, proliferation and ROS production were significantly lower in samples from whole body Nox4 knockout mice (Nox4-/-) and conditional knockout (CKO) mice with depletion of Nox4 in the limb bud mesenchyme compared with those from control mice (Nox4fl/fl), but they were reversed after 9 passages. In both sexes, bone volume, trabecular number and bone mineral density were significantly lower in 3-week old CKO and Nox4-/- mice compared with Nox4fl/fl controls. This was reflected in serum levels of bone formation markers alkaline phosphatase (ALP) and procollagen 1 intact N-terminal propeptide (P1NP). However, under-developed bone formation in 3-week old CKO and Nox4-/- mice quickly caught up to levels of control mice by 6-week of age, remained no different at 13-week of age, and was reversed in 32-week old male mice. Osteoclastogenesis showed no differences among groups, however, CTX1 reflecting osteoclast activity was significantly higher in 3-week old male CKO and Nox4-/- mice compared with control mice, and significantly lower in 32-week old Nox4-/- mice compared with control mice. These data suggest that Nox4 expression and ROS signaling in bone and osteoblastic cells coordinately play a role on osteoblast differentiation, proliferation and maturation.
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Project description:Within the family of NADPH oxidases, Nox4 is unique as it is predominantly localized in the endoplasmic reticulum, has constitutive activity and generates H2O2. We hypothesize that these features are consequences of a so far unidentified Nox4-interacting protein. Interacting proteins were screened by quantitative SILAC-Co-immunoprecipitation in HEK293 cells stably overexpressing Nox4. By this technique, several interacting proteins were identified with calnexin showing the most robust interaction.
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Project description:Hypoxic stress is a feature of rapidly growing thyroid tumors. Cancer progression is thought to be driven by reactive oxygen species (ROS) induced hypoxia adaptation. NADPH oxidases (NOXs), which produce ROS as their primary and sole function, has become of particular interest in thyroid malignancy. NOX4 was demonstrated to be upregulated in papillary thyroid cancers, functioning as a mitochondrial energetic sensor to modulate ATP levels, mediating overproduction of ROS induced by IL-δ, inversely correlating to thyroid differentiation. In this study, we analyzed hypoxia-treated BCPAP cells transfected with siRNA against NOX4. Results provides insight into the role of NOX4 in hypoxia adaptation.
2020-10-31 | GSE160491 | GEO
Project description:Within the family of NADPH oxidases, Nox4 is unique as it is predominantly localized in the endoplasmic reticulum, has constitutive activity and generates H2O2. We hypothesize that these features are consequences of a so far unidentified Nox4-interacting protein. Blue native gel electrophoresis of solubilized membranes from HEK293 cells (overexpressing Nox4) separated macromolecular complexes containing Nox4. The combination of native gel electrophoresis and quantitative mass spectrometry was applied to identify proteins that co-migrate with Nox4. In addition, the data set contains information about macromolecular protein complexes in human cellular membranes that are stable to the solubilization with digitonin.
2017-04-07 | PXD003509 | Pride
Project description:The NRF2 transcription factor is a key regulator of the cellular antioxidant response, and pharmacological NRF2 activation is a promising strategy for the prevention of age-related diseases. Here we show, however, that genetic activation of Nrf2 in skin fibroblasts leads to the production of a matrisome, which is similar to aged skin and characterized by reduced synthesis and deposition of selected matrix proteins, including the major skin collagens. Mechanistically, the production of an aging matrisome results from Nrf2-mediated overexpression of microRNAs (miRs), which directly suppress collagen expression independently of myofibroblast differentiation. This is functionally important, as Nrf2 activation in fibroblasts caused structural abnormalities of the dermal ECM and increased the susceptibility to skin tearing, similar to aged skin. Activation of endogenous NRF2 was observed in human skin from elderly individuals in vitro and in vivo. These data implicate a key role for activated NRF2 in controlling age-related molecular and biomechanical skin alterations.
2022-09-20 | GSE180484 | GEO
Project description:Reactive oxygen species (ROS) play important roles as second messengers in a wide array of cellular processes including differentiation of stem cells. We identified Nox4 as the major ROS generating enzyme whose expression is induced during differentiation of embryoid body (EB) into cells of all three germ layers. The role of Nox4 was examined using iPS cells generated from Nox4 -/- mouse. Differentiation markers showed significantly reduced expression levels consistent with the importance of Nox4-generated ROS during this process. From transcriptomic analyses, we found insulin-like growth factor 2 (IGF2), a member of a gene family extensively involved in embryonic development, as one of the most down-regulated genes. Indeed, addition of IGF2 to culture partly restored the differentiation efficiency of Nox4-/- iPS cells. Our results reveal an important signaling axis mediated by ROS in control of crucial events during differentiation of pluripotent stem cells.
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