Oxidative Stress with an Activation of the Renin-Angiotensin System in Human Vascular Endothelial Cells as a Novel Mechanism of Uric Acid-Induced Endothelial Dysfunction
Abstract
AIMS: Oxidative stress is known to be a major mechanism of endothelial dysfunction, which plays a key role in the development of cardiovascular disease. Although uric acid is one of the most important antioxidants, recent studies have suggested that uric acid may have a causal role in endothelial dysfunction. In order to understand the paradoxical association of uric acid with oxidative stress and vascular disease, we investigated whether uric acid induced oxidative stress in human vascular endothelial cells. We also examined whether uric acid-induced changes in redox status were related to aging and death of endothelial cells or an activation of local renin-angiotensin system, another mediator of endothelial dysfunction. METHODS: Endothelial senescence and apoptosis were evaluated by senescence-associated beta-galactosidase staining and annexin V-propidium iodide staining in primary isolated human umbilical vein endothelial cells (HUVECs). Production of reactive oxygen species was assessed by dichlorofluorescein diacetate staining. mRNA expression of angiotensinogen, angiotensin-converting enzyme and the receptors of angiotensin II was evaluated by real-time PCR, and angiotensin II levels were measured in uric acid-stimulated HUVECs. RESULTS: Uric acid-induced senescence and apoptosis in HUVECs at concentrations more than 6 and 9 mg/dl, respectively. Uric acid-induced alterations in cell proliferation, senescence and apoptosis were blocked by probenecid, enalaprilat or telmisartan. Uric acid significantly increased production of reactive oxygen species beginning at 5 min, and uric acid-induced senescence and apoptosis of HUVECs were ameliorated by N-acetylcysteine or tempol. Uric acid also upregulated the expression of angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors and increased angiotensin II levels, which was ameliorated with tempol. CONCLUSION: Uric acid-induced aging and death of human endothelial cells are medicated by local activation of oxidative stress and the renin-angiotensin system, which provides a novel mechanism of uric acid-induced endothelial dysfunction. Therapies targeting uric acid maybe beneficial in cardiovascular disease.
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Lignans inhibit NADPH oxidase activity and upregulate antioxidant genes such as SOD1, SOD2, catalase, and DNA repairing genes.
“In fact, they can suppress aging phenotypes in Drosophila adults, inhibit NADPH oxidase activity and upregulate antioxidant genes, such as SOD1, SOD2, catalase, and DNA repairing genes [221,404].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [221]
Lignans can suppress aging phenotypes in Drosophila adults.
“In fact, they can suppress aging phenotypes in Drosophila adults, inhibit NADPH oxidase activity and upregulate antioxidant genes, such as SOD1, SOD2, catalase, and DNA repairing genes [221,404].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [221]
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- Authors
- Yu, M.-A., Sánchez-Lozada, L. G., Johnson, R. J., & Kang, D.-H.
- Affiliations
- Ewha Womans University (KR)
- University of Colorado Denver (US)
- Corresponding author
- Kang, Duk-Hee
- Venue
- Journal of Hypertension
- Published
- 2010-06
- Volume
- 28
- Issue
- 6
- Pages
- 1234-1242
- ISSN
- 0263-6352 (ISSN-L)
- OpenAlex
- W2021959778
- Cited by
- 626
- References
- 44
- Citations by year
- 2026: 16 · 2025: 50 · 2024: 61 · 2023: 56 · 2022: 49 · 2021: 63 · 2020: 44 · 2019: 37 · 2018: 36 · 2017: 37 · 2016: 31 · 2015: 29 · 2014: 34 · 2013: 37 · 2012: 20
- FWCI
- 20.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- uric acid, endothelial dysfunction, oxidative stress, renin-angiotensin system, vascular endothelial cells, endothelial cell senescence, endothelial cell apoptosis, reactive oxygen species, angiotensin II, angiotensinogen, angiotensin-converting enzyme, angiotensin II receptor, probenecid, enalaprilat, telmisartan, tempol, N-acetylcysteine, cardiovascular disease
- MeSH terms
- Cells, Cultured, Endothelium, Vascular, Humans, Renin-Angiotensin System, Uric Acid, Polymerase Chain Reaction, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Cell Proliferation
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