ArticleFree radical biology & medicine2016
NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis.
Article in Free radical biology & medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 63 citations in OpenAlex.
- An overview of the role of platelets in vascular disease associated with diabetes mellitus.Hormones (Athens, Greece) · 2026Review
- Sodium-Glucose Cotransporter 2 Inhibitor Ameliorate Angiotensin II-Induced Hypertension and Vascular Injury by Upregulating FGF21.Inflammation · 2025Article
- The Dual Role of Oxidative Stress in Atherosclerosis and Coronary Artery Disease: Pathological Mechanisms and Diagnostic Potential.Antioxidants (Basel, Switzerland) · 2025Review
- Delineating the NOX-Mediated Promising Therapeutic Strategies for the Management of Various Cardiovascular Disorders: A Comprehensive Review.Current vascular pharmacology · 2025Review
- NADPCurrent medicinal chemistry · 2025Review
- Article
- Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes.Antioxidants (Basel, Switzerland) · 2024Article
- Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.Frontiers in immunology · 2024Article
- Mechanisms modulating foam cell formation in the arterial intima: exploring new therapeutic opportunities in atherosclerosis.Frontiers in cardiovascular medicine · 2024Review
- Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging.Archives of toxicology · 2023Review
- The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction.Cardiovascular diabetology · 2023Review
- Nox4 as a novel therapeutic target for diabetic vascular complications.Redox biology · 2023Review
- Review
- WELL-POSEDNESS OF A MATHEMATICAL MODEL OF DIABETIC ATHEROSCLEROSIS.Journal of mathematical analysis and applications · 2022Article
- Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress.Antioxidants (Basel, Switzerland) · 2021Review
- Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future.Antioxidants (Basel, Switzerland) · 2021Review
- Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Association of changes of retinal vessels diameter with ocular blood flow in eyes with diabetic retinopathy.Scientific reports · 2021Article
- Ferroptosis Signaling and Regulators in Atherosclerosis.Frontiers in cell and developmental biology · 2021Review
- A Novel Resveratrol Analog Upregulates SIRT1 Expression and Ameliorates Neointima Formation.Frontiers in cardiovascular medicine · 2021Article
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
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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