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Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits.
Open accessAbstract
Reactive oxygen species play a central role in vascular inflammation and atherogenesis, with enhanced superoxide (O2.-) production contributing significantly to impairment of nitric oxide (.NO)-dependent relaxation of vessels from cholesterol-fed rabbits. We investigated potential sources of O2.- production, which contribute to this loss of endothelium-dependent vascular responses. The vasorelaxation elicited by acetylcholine (ACh) in phenylephrine-contracted, aortic ring segments was impaired by cholesterol feeding. Pretreatment of aortic vessels with either heparin, which competes with xanthine oxidase (XO) for binding to sulfated glycosaminoglycans, or the XO inhibitor allopurinol resulted in a partial restoration (36-40% at 1 muM ACh) of ACh-dependent relaxation. Furthermore, O2.(-)-dependent lucigenin chemiluminescence, measured in intact ring segments from hypercholesterolemic rabbits, was decreased by addition of heparin, allopurinol or a chimeric, heparin-binding superoxide dismutase. XO activity was elevated more than two-fold in plasma of hypercholesterolemic rabbits. Incubation of vascular rings from rabbits on a normal diet with purified XO (10 milliunits/ml) also impaired .NO-dependent relaxation but only in the presence of purine substrate. As with vessels from hypercholesterolemic rabbits, this effect was prevented by heparin and allopurinol treatment. We hypothesize that increases in plasma cholesterol induce the release of XO into the circulation, where it binds to endothelial cell glycosaminoglycans. Only in hypercholesterolemic vessels is sufficient substrate available to sustain the production of O2.- and impair NO-dependent vasorelaxation. Chronically, the continued production of peroxynitrite, (ONOO-) which the simultaneous generation of NO and O2.- implies, may irreversibly impair vessel function.
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“In addition, BH4 plays a critical role in the catalytic cycle of NOS (87, 204, 377, 904, 933, 1000, 1007).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1007]
In the citing paper
“Thus, not only is the NO synthesis completely abolished but the protein also becomes an oxidase, generating superoxide instead of NO (191, 972, 1007) (Table 6).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1007]
In the citing paper
“Mechanistically, when NOS binds BH2 instead of BH4, the ferrous/oxy heme cannot hydroxylate l-arginine to NG-hydroxy-l-arginine, NO synthesis is blocked, and the oxygen is eventually oxidized to superoxide.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1007]
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Metadata
- Authors
- White, C. R., Darley-Usmar, V, Berrington, W. R., McAdams, M., Gore, J. Z., Thompson, J. A., Parks, D. A., Tarpey, M. M., & Freeman, B. A.
- Affiliations
- University of Alabama at Birmingham (US)
- Department of Medicine, University of Alabama at Birmingham 35294, USA.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-08-06
- Volume
- 93
- Issue
- 16
- Pages
- 8745-8749
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC38744
- OpenAlex
- W2012018808
- Cited by
- 367
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 12 · 2017: 12 · 2016: 9 · 2015: 10 · 2014: 17 · 2013: 7 · 2012: 5
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5k08hl003457-04, 5p01hl048676-05, 5r01hl051245-05)
- National Heart, Lung, and Blood Institute (P01 HL 48676, R01 HL 51245, KO8-HL03457)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- xanthine oxidase, hypercholesterolemia, reactive oxygen species, superoxide, endothelial dysfunction, allopurinol, heparin, glycosaminoglycans, peroxynitrite, atherosclerosis, acetylcholine, cholesterol-fed rabbits
- MeSH terms
- Acetylcholine, Animals, Endothelium, Vascular, Glycosaminoglycans, Hypercholesterolemia, Luminescent Measurements, Muscle, Smooth, Vascular, Nitric Oxide, Rabbits, Superoxides, Vasodilation, Xanthine Oxidase, In Vitro Techniques
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