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Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits
C R White1, V Darley-Usmar, W R Berrington
1Department of Medicine, University of Alabama at Birmingham 35294, USA.
Summary
High cholesterol impairs blood vessel function by increasing superoxide production from xanthine oxidase (XO). Inhibiting XO or blocking its binding partially restores nitric oxide (NO)-dependent relaxation, suggesting XO as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Atherosclerosis Research
Background:
- Reactive oxygen species, particularly superoxide (O2.-), are implicated in vascular inflammation and atherosclerosis.
- Enhanced superoxide production impairs nitric oxide (NO)-dependent vasodilation, a key factor in endothelial function.
- Cholesterol feeding in rabbits leads to impaired acetylcholine (ACh)-induced vasorelaxation.
Purpose of the Study:
- To investigate the sources of superoxide production contributing to the loss of endothelium-dependent vascular responses in hypercholesterolemia.
- To determine the role of xanthine oxidase (XO) in mediating vascular dysfunction associated with high cholesterol.
- To explore potential therapeutic strategies targeting XO for restoring vascular function.
Main Methods:
- Measurement of acetylcholine-induced vasorelaxation in aortic ring segments from normal and cholesterol-fed rabbits.
- Assessment of superoxide production using lucigenin chemiluminescence.
- Enzymatic assays to determine xanthine oxidase (XO) activity in plasma and vascular tissues.
- Pharmacological interventions using heparin, allopurinol (XO inhibitor), and superoxide dismutase.
Main Results:
- Cholesterol feeding significantly impaired ACh-dependent vasorelaxation, which was partially restored by heparin or allopurinol.
- Superoxide production, measured by chemiluminescence, was reduced by heparin, allopurinol, and superoxide dismutase in hypercholesterolemic vessels.
- XO activity was elevated in the plasma of hypercholesterolemic rabbits, and purified XO impaired vasorelaxation in normal vessels.
Conclusions:
- Increased plasma cholesterol likely induces XO release, leading to its binding to endothelial glycosaminoglycans.
- Sufficient substrate availability in hypercholesterolemic conditions sustains XO-mediated superoxide production, impairing NO-dependent vasorelaxation.
- Chronic peroxynitrite formation may result from simultaneous NO and O2.- generation, leading to irreversible vascular damage.