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Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during
Alyson A Miller1, T Michael De Silva, Courtney P Judkins
1Department of Pharmacology, Monash University, Clayton, Victoria, Australia. alyson.miller@med.monash.edu.au
Stroke
|February 20, 2010
Summary
Hypercholesterolemia increases superoxide production in cerebral arteries via Nox2-NADPH oxidase, impairing nitric oxide function. This occurs even without lesions and is linked to p47phox subunit expression.
Area of Science:
- Vascular Biology
- Cardiovascular Research
- Biochemistry
Background:
- Hypercholesterolemia is a risk factor for cardiovascular diseases.
- Oxidative stress, particularly superoxide production, plays a role in vascular dysfunction.
- Nox2-NADPH oxidase is a key source of superoxide in various cell types.
Purpose of the Study:
- To investigate if hypercholesterolemia elevates superoxide production in cerebral arteries.
- To determine if this superoxide production impairs nitric oxide function.
- To identify the role of Nox2-NADPH oxidase in these changes.
Main Methods:
- Utilized wild-type, apolipoprotein E-deficient (ApoE(-/-)), and Nox2(-/-)/ApoE(-/-) mice on a high-fat diet.
- Measured superoxide production in cerebral arteries using chemiluminescence.
- Assessed nitric oxide function via N(omega)-nitro-L-arginine methyl ester (L-NAME) induced contractions and Western blotting for key proteins.
Main Results:
- Apolipoprotein E-deficient mice exhibited significantly increased superoxide production and reduced nitric oxide function compared to wild-type mice.
- These changes were absent in Nox2(-/-)/ApoE(-/-) mice, indicating Nox2 dependency.
- Increased p47phox expression was observed in hypercholesterolemic mice, without changes in Nox2, eNOS, or SODs.
Conclusions:
- Elevated superoxide production and reduced nitric oxide-mediated relaxation occur in cerebral arteries of hypercholesterolemic mice.
- These vascular changes are primarily driven by increased Nox2-NADPH oxidase activity.
- Increased expression of the p47phox subunit may underlie the enhanced Nox2 activity in hypercholesterolemia.
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