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NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-β1–Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts
Abstract
Human cardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-β1 (TGF-β1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle α-actin (SM α-actin) de novo and produce extracellular matrix. We hypothesized that TGF-β1–stimulated conversion of fibroblasts to myofibroblasts requires reactive oxygen species derived from NAD(P)H oxidases (Nox). We found that TGF-β1 potently upregulates the contractile marker SM α-actin mRNA (7.5±0.8-fold versus control). To determine whether Nox enzymes are involved, we first performed quantitative real time polymerase chain reaction and found that Nox5 and Nox4 are abundantly expressed in cardiac fibroblasts, whereas Nox1 and Nox2 are barely detectable. On stimulation with TGF-β1, Nox4 mRNA is dramatically upregulated by 16.2±0.8-fold (n=3, P <0.005), whereas Nox5 is downregulated. Small interference RNA against Nox4 downregulates Nox4 mRNA by 80±5%, inhibits NADPH-driven superoxide production in response to TGF-β1 by 65±7%, and reduces TGF-β1–induced expression of SM α-actin by 95±2% (n=6, P <0.05). Because activation of small mothers against decapentaplegic (Smads) 2/3 is critical for myofibroblast conversion in response to TGF-β1, we also determined whether Nox4 affects Smad 2/3 phosphorylation. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-β1 stimulation of Smad 2/3 phosphorylation by 75±5% and 68±3%, respectively (n=7, P <0.0001). We conclude that Nox 4 mediates TGF-β1–induced conversion of fibroblasts to myofibroblasts by regulating Smad 2/3 activation. Thus, Nox4 may play a critical role in the pathological activation of cardiac fibroblasts in cardiac fibrosis associated with human heart failure.
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“In a final note, it should be also considered that although NOX4 activity has been shown to reduce fibrosis in atherosclerosis (230), it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues (110, 201, 416, 596, 820).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [201]
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“The expression of NOX4 is upregulated by TGF-β (201, 906).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [201]
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Metadata
- Authors
- Cucoranu, I., Clempus, R., Dikalova, A., Phelan, P. J., Ariyan, S., Dikalov, S., & Sorescu, D.
- Affiliations
- Emory University (US)
- Venue
- Circulation Research
- Published
- 2005-10-28
- Volume
- 97
- Issue
- 9
- Pages
- 900-907
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2162514162
- Cited by
- 786
- References
- 41
- Citations by year
- 2026: 24 · 2025: 17 · 2024: 19 · 2023: 39 · 2022: 47 · 2021: 35 · 2020: 39 · 2019: 33 · 2018: 42 · 2017: 47 · 2016: 44 · 2015: 52 · 2014: 51 · 2013: 54 · 2012: 52
- FWCI
- 18.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- NOX4, cardiac fibroblasts, myofibroblast differentiation, TGF-β1, myocardial fibrosis, smooth muscle actin, reactive oxygen species, superoxide, Smad2/3 phosphorylation, heart failure, cardiac hypertrophy, extracellular matrix
- MeSH terms
- NADPH Oxidase 4, Actins, Cell Differentiation, Cells, Cultured, Fibroblasts, Fibrosis, Humans, Myocardium, RNA, Messenger, Superoxides, Transforming Growth Factor beta, Reactive Oxygen Species, Immediate-Early Proteins, NADPH Oxidases, Intercellular Signaling Peptides and Proteins, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta1, Connective Tissue Growth Factor
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