High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells
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Recent studies have revealed that vascular cells can produce reactive oxygen species (ROS) through NAD(P)H oxidase, which may be involved in vascular injury. However, the pathological role of vascular NAD(P)H oxidase in diabetes or in the insulin-resistant state remains unknown. In this study, we examined the effect of high glucose level and free fatty acid (FFA) (palmitate) on ROS production in cultured aortic smooth muscle cells (SMCs) and endothelial cells (ECs) using electron spin resonance spectroscopy. Exposure of cultured SMCs or ECs to a high glucose level (400 mg/dl) for 72 h significantly increased the free radical production compared with low glucose level exposure (100 mg/dl). Treatment of the cells for 3 h with phorbol myristic acid (PMA), a protein kinase C (PKC) activator, also increased free radical production. This increase was restored to the control value by diphenylene iodonium, a NAD(P)H oxidase inhibitor, suggesting ROS production through PKC-dependent activation of NAD(P)H oxidase. The increase in free radical production by high glucose level exposure was completely restored by both diphenylene iodonium and GF109203X, a PKC-specific inhibitor. Exposure to palmitate (200 micromol/l) also increased free radical production, which was concomitant with increases in diacylglycerol level and PKC activity. Again, this increase was restored to the control value by both diphenylene iodonium and GF109203X. The present results suggest that both high glucose level and palmitate may stimulate ROS production through PKC-dependent activation of NAD(P)H oxidase in both vascular SMCs and ECs. This finding may be involved in the excessive acceleration of atherosclerosis in patients with diabetes and insulin resistance syndrome.
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FFAs also contribute to a higher production of ROS and inflammation in endothelial cells.
“FFAs also contribute to a higher production of ROS and inflammation in ECs [260].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [260]
Activated PKC promotes oxidative stress by activating NADPH oxidase.
“Activated PKC in turn promotes oxidative stress by activating NADPH oxidase.”
From The Vasculature in Prediabetes (2018) · cites this paper as [66]
FFAs activate NADPH oxidase via PKC to generate ROS.
“FFAs activate NADPH oxidase via PKC to generate ROS.”
From The Vasculature in Prediabetes (2018) · cites this paper as [66]
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- Authors
- Inoguchi, T., Li, P., Umeda, F., Yu, H. Y., Kakimoto, M., Imamura, M., Aoki, T., Etoh, T., Hashimoto, T., Naruse, M., Sano, H., Utsumi, H., & Nawata, H.
- Affiliations
- Kyushu University (JP)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-11-01
- Volume
- 49
- Issue
- 11
- Pages
- 1939-1945
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2109168147
- Cited by
- 1,577
- References
- 57
- Citations by year
- 2026: 23 · 2025: 35 · 2024: 40 · 2023: 50 · 2022: 61 · 2021: 63 · 2020: 61 · 2019: 59 · 2018: 63 · 2017: 55 · 2016: 70 · 2015: 77 · 2014: 86 · 2013: 74 · 2012: 80
- FWCI
- 23.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (11671126)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- reactive oxygen species, NADPH oxidase, protein kinase C, high glucose, free fatty acids, palmitate, aortic smooth muscle cells, endothelial cells, diacylglycerol, oxidative stress, insulin resistance, atherosclerosis
- MeSH terms
- Animals, Aorta, Blood Vessels, Cattle, Cells, Cultured, Electron Spin Resonance Spectroscopy, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Fatty Acids, Nonesterified, Glucose, Indoles, Maleimides, Muscle, Smooth, Vascular, Onium Compounds, Protein Kinase C, Tetradecanoylphorbol Acetate, Reactive Oxygen Species, NADPH Oxidases, Palmitic Acid
About these checks
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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