NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis
Open accessAbstract
Smooth muscle cell (SMC) proliferation and fibrosis contribute to the development of advanced atherosclerotic lesions. Oxidative stress caused by increased production or unphysiological location of reactive oxygen species (ROS) is a known major pathomechanism. However, in atherosclerosis, in particular under hyperglycaemic/diabetic conditions, the hydrogen peroxide-producing NADPH oxidase type 4 (NOX4) is protective. Here we aim to elucidate the mechanisms underlying this paradoxical atheroprotection of vascular smooth muscle NOX4 under conditions of normo- and hyperglycaemia both in vivo and ex vivo. Following 20-weeks of streptozotocin-induced diabetes, Apoe(-/-) mice showed a reduction in SM-alpha-actin and calponin gene expression with concomitant increases in platelet-derived growth factor (PDGF), osteopontin (OPN) and the extracellular matrix (ECM) protein fibronectin when compared to non-diabetic controls. Genetic deletion of Nox4 (Nox4(-/)(-)Apoe(-/-)) exacerbated diabetes-induced expression of PDGF, OPN, collagen I, and proliferation marker Ki67. Aortic SMCs isolated from NOX4-deficient mice exhibited a dedifferentiated phenotype including loss of contractile gene expression, increased proliferation and ECM production as well as elevated levels of NOX1-associated ROS. Mechanistic studies revealed that elevated PDGF signalling in NOX4-deficient SMCs mediated the loss of calponin and increase in fibronectin, while the upregulation of NOX1 was associated with the increased expression of OPN and markers of proliferation. These findings demonstrate that NOX4 actively regulates SMC pathophysiological responses in diabetic Apoe(-/-) mice and in primary mouse SMCs through the activities of PDGF and NOX1.
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In general, NOX4 shows protective effects in ApoE−/− mice.
“In general, NOX4 shows protective effects in ApoE−/− mice (194, 229, 230, 379, 552, 838).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [230]
Although NOX4 activity has been shown to reduce fibrosis in atherosclerosis, it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues.
“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 [230]
NOX4-derived hydrogen peroxide exhibits anti-atherosclerotic effects by smooth muscle cell regulation in diabetic mice.
“In contrast with this study, NOX4-derived hydrogen peroxide exhibited anti-atherosclerotic effects by smooth muscle cell regulation in diabetic mice (Di Marco et al. 2016; Cortinovis et al. 2022).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Di Marco et al. 2016
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- Authors
- Di Marco, E., Gray, S. P., Kennedy, K., Szyndralewiez, C., Lyle, A. N., Lassègue, B., Griendling, K. K., Cooper, M. E., Schmidt, H. H. H. W., & Jandeleit-Dahm, K. A. M.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Emory University (US)
- Maastricht University (NL)
- Corresponding author
- Jandeleit-Dahm, Karin A.M.
- ORCID
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 97
- Pages
- 556-567
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC5446082
- OpenAlex
- W2478055166
- Cited by
- 67
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 9 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 3
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- National Health & Medical Research Council (NHMRC)
- Juvenile Diabetes Research Foundation (JDRF)
- Diabetes Australia Research Trust
- Australian Diabetes Society Skip Martin Early Career Fellowship
- National Heart Foundation Postgraduate Scholarship
- HHHWS
- EU Marie Curie International Reintegration Grant and the ERC (30983347E RADMED)
- National Institute of Health (HL038206, HL095070)
- NHMRC Senior Research and Senior Principal Fellowships
- Victorian Government¹s Operational Infrastructure
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX4, reactive oxygen species, diabetic atherosclerosis, vascular smooth muscle cells, smooth muscle cell proliferation, vascular fibrosis, hyperglycemia, NADPH oxidase, NOX1, platelet-derived growth factor, osteopontin, fibronectin, extracellular matrix, calponin, smooth muscle cell dedifferentiation, oxidative stress, atheroprotection
- MeSH terms
- NADPH Oxidase 1, NADPH Oxidase 4, Becaplermin, Animals, Aorta, Cells, Cultured, Diabetes Mellitus, Experimental, Fibrosis, Male, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Superoxides, Reactive Oxygen Species, Mice, Knockout, Proto-Oncogene Proteins c-sis, Myocytes, Smooth Muscle, Cell Proliferation, Atherosclerosis, Osteopontin, Mice, 129 Strain
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