Endothelial Regulation of Vasomotion in ApoE-Deficient Mice: Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin
Open accessAbstract
Background —Altered endothelial cell nitric oxide (NO · ) production in atherosclerosis may be due to a reduction of intracellular tetrahydrobiopterin, which is a critical cofactor for NO synthase (NOS). In addition, previous literature suggests that inactivation of NO · by increased vascular production superoxide (O 2 ·− ) also reduces NO · bioactivity in several disease states. We sought to determine whether these 2 seemingly disparate mechanisms were related. Methods and Results —Endothelium-dependent vasodilation was abnormal in aortas of apoE-deficient (apoE −/− ) mice, whereas vascular superoxide production (assessed by 5 μmol/L lucigenin) was markedly increased. Treatment with either liposome-entrapped superoxide dismutase or sepiapterin, a precursor to tetrahydrobiopterin, improved endothelium-dependent vasodilation in aortas from apoE −/− mice. Hydrogen peroxide had no effect on the decay of tetrahydrobiopterin, as monitored spectrophotometrically. In contrast, superoxide modestly and peroxynitrite strikingly increased the decay of tetrahydrobiopterin over 500 seconds. Luminol chemiluminescence, inhibitable by the peroxynitrite scavengers ebselen and uric acid, was markedly increased in apoE −/− aortic rings. In vessels from apoE −/− mice, uric acid improved endothelium-dependent relaxation while having no effect in vessels from control mice. Treatment of normal aortas with exogenous peroxynitrite dramatically increased vascular O 2 ·− production, seemingly from eNOS, because this effect was absent in vessels lacking endothelium, was blocked by NOS inhibition, and did not occur in vessels from mice lacking eNOS. Conclusions —Reactive oxygen species may alter endothelium-dependent vascular relaxation not only by the interaction of O 2 ·− with NO · but also through interactions between peroxynitrite and tetrahydrobiopterin. Peroxynitrite oxidation of tetrahydrobiopterin may represent a pathogenic cause of “uncoupling” of NO synthase.
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Use of p47phox−/− as a surrogate for NOX2 deletion is partly limited by the involvement of p47phox in other protein complexes, including noncanonical activation of NOX1 and interaction with protein disulfide isomerase.
“It should be noted that the use of p47phox−/− as a surrogate for the NOX2 deletion is partly limited by the involvement of p47phox in other protein complexes, including not only the noncanonical activation of NOX1, as already mentioned above but also its interaction with protein disulfide isomerase (214, 559).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [559]
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- Authors
- Laursen, J. B., Somers, M., Kurz, S., McCann, L., Warnholtz, A., Freeman, B. A., Tarpey, M., Fukai, T., & Harrison, D. G.
- Affiliations
- Emory University (US)
- From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital, Atlanta, Ga (J.B.L., M.S., S.K., L.M., A.W., T.F., D.G.H.); the Department of Anesthesia, University of Alabama, Birmingham (B.A.F., M.T.); and Medical Department B, Division of Cardiology, Rigshospitalet, Denmark (J.B.L.).
- Venue
- Circulation
- Published
- 2001-03-06
- Volume
- 103
- Issue
- 9
- Pages
- 1282-1288
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2050548878
- Cited by
- 721
- References
- 29
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 15 · 2022: 15 · 2021: 14 · 2020: 17 · 2019: 20 · 2018: 19 · 2017: 17 · 2016: 23 · 2015: 26 · 2014: 30 · 2013: 28 · 2012: 45
- FWCI
- 30.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1p01hl048667-01, 5p01hl048676-05)
- National Heart, Lung, and Blood Institute (R01HL039006, R01HL39006, HL-48667, HL48676)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- endothelial dysfunction, vasomotion, ApoE-deficient mice, nitric oxide, tetrahydrobiopterin, peroxynitrite, superoxide, endothelium-dependent vasodilation, atherosclerosis, eNOS uncoupling, superoxide dismutase, sepiapterin, uric acid, reactive oxygen species
- MeSH terms
- Calcimycin, Acetylcholine, Animals, Aorta, Thoracic, Apolipoproteins E, Biopterins, Dose-Response Relationship, Drug, Endothelium, Vascular, Female, Nitroglycerin, Ionophores, Male, Mice, Inbred C57BL, Nitrates, Pteridines, Pterins, Superoxides, Vasodilation, Vasodilator Agents, Mice, Knockout, Nitric Oxide Synthase, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, In Vitro Techniques
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