Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5)
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AIMS: NADPH oxidase (NOX) is the primary source of reactive oxygen species (ROS) in vascular smooth muscle cells (SMC) and is proposed to play a key role in redox signaling involved in the pathogenesis of cardiovascular disease. Growth factors and cytokines stimulate coronary SMC (CSMC) phenotypic modulation, proliferation, and migration during atherosclerotic plaque development and restenosis. We previously demonstrated that increased expression and activity of intermediate-conductance Ca(2+)-activated K(+) channels (KCNN4) is necessary for CSMC phenotypic modulation and progression of stenotic lesions. Therefore, the purpose of this study was to determine whether NOX is required for KCNN4 upregulation induced by mitogenic growth factors. METHODS AND RESULTS: Dihydroethidium micro-fluorography in porcine CSMCs demonstrated that basic fibroblast growth factor (bFGF) increased superoxide production, which was blocked by the NOX inhibitor apocynin (Apo). Apo also blocked bFGF-induced increases in KCNN4 mRNA levels in both right coronary artery sections and CSMCs. Similarly, immunohistochemistry and whole cell voltage clamp showed bFGF-induced increases in CSMC KCNN4 protein expression and channel activity were abolished by Apo. Treatment with Apo also inhibited bFGF-induced increases in activator protein-1 promoter activity, as measured by luciferase activity assay. qRT-PCR demonstrated porcine coronary smooth muscle expression of NOX1, NOX2, NOX4, and NOX5 isoforms. Knockdown of NOX5 alone prevented both bFGF-induced upregulation of KCNN4 mRNA and CSMC migration. CONCLUSIONS: Our findings provide novel evidence that NOX5-derived ROS increase functional expression of KCNN4 through activator protein-1, providing another potential link between NOX, CSMC phenotypic modulation, and atherosclerosis.
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NOX5 appears to modulate proliferation and cell migration processes.
“NOX5 also appears to modulate proliferation and cell migration processes (371, 719).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [371]
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Flagged first, then by citations
1 of the 101 references couldn’t be matched to a known paper.
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Oxidative Stress and Hypertension
Griendling, K. K., Camargo, L. L., Rios, F. J. O., Alves-Lopes, R., Montezano, A. C. I., & Touyz, R. M. (2021) · Circulation Research · doi:10.1161/circresaha.121.318063 · Cited by 592 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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Interrelation between ROS and Ca2+ in aging and age-related diseases
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Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth
Jackson, W. F. (2017) · Advances in pharmacology · doi:10.1016/bs.apha.2016.07.001 · Cited by 151 · see citing works
Nox, Reactive Oxygen Species and Regulation of Vascular Cell Fate
Burtenshaw, D., Hakimjavadi, R., Redmond, E. M., & Cahill, P. A. (2017) · Antioxidants · doi:10.3390/antiox6040090 · Cited by 136 · see citing works
NOX5: Molecular biology and pathophysiology
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Oxidative Stress in Kidney Injury and Hypertension
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Are reactive oxygen species still the basis for diabetic complications?
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Microvascular NADPH oxidase in health and disease
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Redox control of vascular smooth muscle cell function and plasticity
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Sylvester, A. L., Zhang, D. X., Ran, S., & Zinkevich, N. S. (2022) · Biomolecules · doi:10.3390/biom12060823 · Cited by 62 · see citing works
Recent advances in therapeutic strategies that focus on the regulation of ion channel expression
Ohya, S., Kito, H., Hatano, N., & Muraki, K. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.02.001 · Cited by 49 · see citing works
Liu, F., Zhu, X., Jiang, X., Li, S., & Lv, Y.-C. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.06.010 · Cited by 40 · see citing works
The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells
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Enzymatic regulation and functional relevance of NOX5
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Implications of NADPH oxidase 5 in vascular diseases
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Self-citationGenetic silencing of K Ca 3.1 inhibits atherosclerosis in ApoE null mice
Alam, P., Tharp, D. L., Bowles, H. J., Grisanti, L. A., Bui, M., Bender, S. B., & Bowles, D. K. (2025) · Channels · doi:10.1080/19336950.2025.2538864 · Cited by 4 · see citing works
Self-citationNADPH Oxidase 5 (NOX5) Upregulates MMP-10 Production and Cell Migration in Human Endothelial Cells
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Nox5: Molecular Regulation and Pathophysiology
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Genetic silencing of K Ca 3.1 inhibits atherosclerosis in ApoE null micePreprint
Alam, P., Tharp, D. L., Bowles, H. J., Grisanti, L. A., Bui, M., Bender, S. B., & Bowles, D. K. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.11.628017 · Cited by 1 · see citing works
Self-citationOral anticoagulants as double-edged swords
Petrus, V. G. R. H. (2020) · doi:10.26481/dis.20200708rg
Baek, S., Kang, M. S., Raffa, G. M., Pisano, C., Nuzzi, V., Kowalewski, M., Suwalski, P., & Urbanowicz, T. K. (2026) · Antioxidants · doi:10.3390/antiox15101222
- Authors
- Gole, H. K. A., Tharp, D. L., & Bowles, D. K.
- Affiliations
- University of Missouri (US)
- Corresponding author
- Bowles, Douglas K.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-21
- Volume
- 9
- Issue
- 8
- Pages
- e105337
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4140784
- OpenAlex
- W2003776935
- Cited by
- 36
- References
- 101
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 4
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (RR1 8276, HL-52490)
- National Heart, Lung, and Blood Institute (HL-52490, P01HL052490)
- National Center for Research Resources (R24RR018276, RR-18276)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- KCNN4, NADPH oxidase 5, coronary artery smooth muscle cells, reactive oxygen species, superoxide, basic fibroblast growth factor, apocynin, activator protein-1, atherosclerosis, restenosis, smooth muscle cell migration, redox signaling
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Coronary Vessels, Gene Expression Regulation, Isoenzymes, Muscle, Smooth, Vascular, RNA, Messenger, Swine, Up-Regulation, Gene Expression, Fibroblast Growth Factor 2, Reactive Oxygen Species, Transcription Factor AP-1, NADPH Oxidases, Potassium Channels, Calcium-Activated, Gene Knockdown Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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