The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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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Citations
Cites
NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
Griendling, K. K., Sorescu, D., & Ushio-Fukai, M. (2000) · Circulation Research · doi:10.1161/01.res.86.5.494 · Cited by 2,886
Self-citationMassagué, J. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043051 · Cited by 1,925
Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase
Li, Y., Huang, T.-T., Carlson, E. J., Melov, S., Ursell, P. C., Olson, J. L., Noble, L. J., Yoshimura, M. P., Berger, C., Chan, P. H., et al. (1995) · Nature Genetics · doi:10.1038/ng1295-376 · Cited by 1,789
Cell transformation by the superoxide-generating oxidase Mox1
Suh, Y.-A., Arnold, R. S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A. B., Griendling, K. K., & Lambeth, J. D. (1999) · Nature · doi:10.1038/43459 · Cited by 1,480
Self-citationKip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.
Reynisdóttir, I., Polyak, K., Iavarone, A., & Massagué, J. (1995) · Genes & Development · doi:10.1101/gad.9.15.1831 · Cited by 962
Superoxide Production and Expression of Nox Family Proteins in Human Atherosclerosis
Sorescu, D., Weiss, D., Lassègue, B., Clempus, R. E., Szöcs, K., Sorescu, G. P., Valppu, L., Quinn, M. T., Lambeth, J. D., Vega, J. D., et al. (2002) · Circulation · doi:10.1161/01.cir.0000012917.74432.66 · Cited by 847
Self-citationIdentification of Renox, an NAD(P)H oxidase in kidney
Geiszt, M., Kopp, J. B., Várnai, P., & Leto, T. L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130135897 · Cited by 840
Lassègue, B., Sorescu, D., Szöcs, K., Yin, Q., Akers, M., Zhang, Y., Grant, S. L., Lambeth, J. D., & Griendling, K. K. (2001) · Circulation Research · doi:10.1161/hh0901.090299 · Cited by 839
Self-citationIde, T., Tsutsui, H., Kinugawa, S., Utsumi, H., Kang, D., Hattori, N., Uchida, K., Arimura, K., Egashira, K., & Takeshita, A. (1999) · Circulation Research · doi:10.1161/01.res.85.4.357 · Cited by 702
TGF-?1 and angiotensin networking in cardiac remodeling
Rosenkranz, S. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.04.030 · Cited by 682
Cited by
Sorted by citations
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989
“Heart (55, 143) (79, 143, 372, 454, 963) (120, 143, 813) Cardiomyocytes (457) (488, 537, 601, 963) (120) (626) (457) (626) Developing cardiomyocytes (536) (536) (536) (790) Endothelium (537) Fibroblast (176) (176) (176) Phagocytes (560)”
BackgroundFrangogiannis, N. G. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvaa324 · Cited by 1,229
TGF-β signaling in health, disease and therapeutics
Deng, Z., Fan, T. T., Chu, X., Tian, H., Zheng, Y., Li, C., & He, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01764-w · Cited by 1,360
Spinale, F. G. (2007) · Physiological Reviews · doi:10.1152/physrev.00012.2007 · Cited by 1,139
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,147
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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