NADPH oxidase 4 contributes to connective tissue growth factor expression through Smad3-dependent signaling pathway
Abstract
Transforming growth factor-β (TGF-β)/Smad signaling has been implicated in connective tissue growth factor (CTGF) expression in vascular smooth muscle cells (VSMC). Reactive oxygen species (ROS) are involved in activation of TGF-β/Smad signaling. However, detailed mechanisms underlying the process remain unclear. In present study, we demonstrated TGF-β1 strongly induced CTGF expression, Smad3 activation, NADPH oxidase 4 (Nox4) expression and increased ROS production in primary rat VSMC in vitro. NADPH oxidases inhibitor diphenylene iodonium (DPI) eliminated TGF-β1-induced CTGF expression and ROS generation. In addition, small-interfering RNA (siRNA) silencing of Smad3 or Nox4 significantly suppressed TGF-β1-mediated CTGF expression in VSMC. Furthermore, Nox4 silencing or inhibition eliminated TGF-β1-induced Smad3 activation and interaction between Nox4 and Smad3. In vivo studies further identified a positive correlation of Nox4 levels with Smad3 activation and CTGF expression in atherosclerotic arteries of patients and animal models. These data established that a novel mechanistic link of Nox4-dependent activation of Smad3 to increased TGF-β1-induced CTGF in the process of vascular remodeling, which suggested a new potential pathway for therapeutic interventions.
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Oxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels.
“In this context, it has become increasingly appreciated that oxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [595]
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Chronic Inflammation and Coronary Microvascular Dysfunction
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- Authors
- Liu, X.-H., Zhang, Q.-Y., Pan, L.-L., Liu, S.-Y., Xu, P., Luo, X.-L., Zou, S.-L., Xin, H., Qu, L.-F., & Zhu, Y.-Z.
- Affiliations
- Fudan University (CN)
- Macau University of Science and Technology (MO)
- Corresponding author
- Zhu, Yi-Zhun
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 94
- Pages
- 174-184
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2288682813
- Cited by
- 31
- References
- 49
- Citations by year
- 2026: 1 · 2025: 4 · 2023: 3 · 2022: 2 · 2021: 8 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 2
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81470164, 81573420, 81330080)
- Shanghai Committee of Science and Technology of China (14JC1401100)
- National Major Scientific and Technological Special Project (2012ZX09103101-064)
- Education Commission of Shanghai Municipality (ZDSYS14005)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- NOX4, connective tissue growth factor, Smad3, TGF-β1 signaling, reactive oxygen species, vascular smooth muscle cells, diphenyleneiodonium, atherosclerosis, vascular remodeling
- MeSH terms
- NADPH Oxidase 4, Animals, Gene Expression Regulation, Humans, Muscle, Smooth, Vascular, Onium Compounds, Signal Transduction, Reactive Oxygen Species, RNA, Small Interfering, Mice, Rats, Smad3 Protein, Transforming Growth Factor beta1, Connective Tissue Growth Factor, Vascular Remodeling
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